Indole derivatives

ABSTRACT

This invention relates to compounds of formula ##STR1## or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO 2  R 2  or COR 2  wherein R 2  represents hydroxy, methoxy, amino, alkylamino, or dialkylamino; m is zero or an integer 1 or 2; 
     R 1  represents a cycloalkyl, bridged cycloalkyl, heteroaryl, bridged heterocyclic or optionally substituted phenyl or fused bicyclic carbocylic group; 
     A represents a C 1-4  alkylene chain or the chain (CH 2 ) p  Y(CH 2 ) q  wherein Y is O, S(O)n or NR 3  and which chains may be substituted by one or two groups selected from C 1-6  alkyl optionally substituted by hydroxy, amino, alkylamino or dialkylamino, or which chains may be substituted by the group ═O; 
     R 3  represents hydrogen, alkyl or a nitrogen protecting group; 
     n is zero or an integer from 1 to 2; 
     p is zero or an integer from 1 to 3; 
     q is zero or an integer from 1 to 3 with the proviso that the sum of p+q is 1, 2 or 3, which are antagonists of excitatory amino acids, to processes for the preparation and to other use in medicine.

This application is a 371 of PCT/EP94/03359 filed Oct. 12, 1994.

This application is a 371 of PCT/EP94/03359 filed Oct. 12, 1994.

This invention relates to novel indole derivatives to processes fortheir preparation, to pharmaceutical compositions containing them and totheir use in medicine. In particular it relates to indole derivativeswhich are potent and specific antagonists of excitatory amino acids.

U.S. Pat. No. 4960786 discloses that certain known 2-carboxylic indolederivatives are antagonists of excitatory amino acids. EP-A 0396124 alsoteaches certain 2-carboxylic indole derivatives as being therapeuticallyeffective in the treatment of CNS discloses resulting from neurotoxicdamage or neurodegenerative diseases. Further3-substituted-2-carboxyindole derivatives which are useful in thetreatment of neurodegenerative diseases including cerebrovasulardisorders are disclosed in WO92/16205.

We have now found a novel group of 3-substituted-2-carboxyindolederivatives that have a specific antagonist activity at the strychnineinsensitive glycine binding site located con the N-methyl-D-aspartate(NMDA) receptor complex.

Accordingly the present invention provides a compound of formula (I)##STR2## or a salt, or metabolically labile ester thereof wherein Rrepresents a group selected from halogen, alkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy,nitro, cyano, SO₂ R₂ or COR₂ wherein R₂ represents hydroxy, methoxy,amino, alkylamino, or dialkylamino; m is zero or an integer 1 or 2;

R₁ represents a cycloalkyl, bridged cycloalkyl, heteroaryl, bridgedheterocyclic or optionally substituted phenyl or fused bicycliccarbocylic group;

A represents a C₁₋₄ alkylene chain or the chain (CH₂)_(p) Y(CH₂)_(q)wherein Y is O,

S(O)n or NR₃ and which chains may be substituted by one or two groupsselected from C₁₋₆ alkyl optionally substituted by hydroxy, amino,alkylamino or dialkylamino, or which chains may be substituted by thegroup ═O;

R₃ represents hydrogen, alkyl or a nitrogen protecting group;

n is zero or an integer from 1 to 2;

p is zero or an integer from 1 to 3;

q is zero or an integer from 1 to 3 with the proviso that the sum of p+qis 1, 2 or3.

The compound represented by formula (I) can exist in more than oneisomeric form and all possible is are included in formula (I) unlessotherwise specified. Thus in compounds of formula (I) the exocyclicdouble bond can exist in the cis or trans configuration and theinvention includes both isomers and mixtures thereof.

For use in medicine the salts of the compounds of formula (I) will bephysiologically acceptable thereof. Other salts however may be useful inthe preparation of the compounds of formula (I) or physiologicallyacceptable salts thereof. Therefore unless otherwise stated referencesto salts includes both physiologically acceptable salts andnon-physiologically acceptable salts of compounds of formula (I).

Suitable physiologically acceptable salts of compounds of the inventioninclude base addition salts and where appropriate acid addition salts.Suitable physiologically acceptable base addition salts of compounds offormula (I) include alkali metal or alkaline metal salts such as sodium,potassium, calcium, and magnesium salts, and ammonium salts, formed withamino acids (e.g. lysine and arginine) and organic bases ( e.g.procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methylglucosamine).

Suitable acid addition salts may be formed with organic acid andinorganic acids e.g. hydrochloric acid.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

It will be appreciated that the compound of formula (I) may be producedin vivo by metabolism of a suitable prodrug. Such prodrugs may be forexample physiologically acceptable metabolically labile esters ofcompounds of the general formula (I). These may be formed byesterificaton of the carboxylic acid group in the parent compound ofgeneral formula (I) with where appropriate prior protection of any otherreactive groups present in the molecule followed by deprotection ifrequired. Examples of such metabolically labile esters include C₁₋₄alkyl esters e.g. methyl or t-butyl esters esters, C₃₋₆ alkenyl esterse.g. allyl substituted or unsubstituted aminoalkyl esters (e.g.aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholin)ethyl estersor acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g.pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl,1-acetoxyetyl,1-(1-methoxy-1-methyl)ethylcarbonyloxethyl,1-benzoyloxyethyl,isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl,cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester,cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl,1-(4-tetrahydropyranyloxy)carbonyloxyethyl or1-(4-tetrahydropyranyl)carbonyloxyethyl.

Preferred metabolically labile esters of compounds of formula (I)include C₁₋₄ alkyl esters more particular methyl or ethyl, aminoalkylesters more particular 2-(4'-morpholino)ethyl, or acyloxyalkyl esterse.g. acetoxymethyl, pivaloyloxymethyl, 1-cyclohexyloxycarbonyloxyethylor 1-(4-tetrahydropyranyloxycarbonyloxy)ethyl.

The group R may be at any of the four possible positions on the fusedbenzene ring and when m is 2 the two R groups may be the same ordifferent.

Unless otherwise specified the term alkyl as used herein as a group orpart of a group refers to a straight or branched chain alkyl groupcontaining from 1 to 4 carbon atom examples of such groups includemethyl, ethyl propyl, isopropyl, n-butyl, isobutyl, secondary butyl ortertiary butyl.

The term halogen refers to a fluorine, chlorine bromine or iodine atom.

The term cycloalkyl refers to a C₅₋₇ cycloalkyl group which mayoptionally be substituted by 1 or 2 C₁₋₄ alkyl groups, e.g. cyclopentyl,cyclohexyl, cycloheptyl or 2-methylcyclohexyl.

The term bridged cycloalkyl refers to a group containing from 7 to 10carbon atoms and which is saturated or contains a single double bond.Examples of suitable bridged cycloalkyl groups include adamantyl, suchas 1-adamantyl or 2-adamantyl, noradamantyl, bicyclo(2,2,1)heptanyl suchas 2-norbomanyl, or bicyclo (2,2,1) heptenyl such as 5-norbomenyl.

The term heteroaryl refers to a 5 or 6 membered heteroaryl group inwhich the 5-membered heteroaryl group contains 1 or 2 heteroatomsselected from oxygen, sulphur or nitrogen and 6-membered heteroarylgroup containing 1 or 2 nitrogen atoms, which heteroaryl groups may beoptionally fused to a benzene ring. Examples of suitable heteroarylgroups include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl,pyridinyl, pyrimidinyl and quinolinyl.

The termn bridged heterocylic refers to a bridged heterocyclic ringsystem containing from 7 to 10 ring members selected from carbon, oxygenor nitrogen and which bridged heterocyclic system is saturated orcontains a single double bond. Preferably the bridged heterocyclic groupcontains a single heteroatom selected from oxygen or nitrogen. Examplesof suitable bridged heterocyclic groups include 7-oxa-bicyclo (2,2,1)heptanyl, 7-oxa-bicyclo (2,2,1) heptenyl, 7-aza-bicyclo (2,2,1)heptanyl, 7-aza-bicyclo (2,2,1) heptenyl or 1-azabicyclo (2,2,2) octanylsuch as 3-quinuclidinyl.

The tern fused bicyclic carbocyclic group refers to a 5,6/6,5 or 6,6bicyclic carbocyclic ring system containing 9 or 10 carbon atoms andwhich may be saturated or unsaturated. Examples of such groups includenaphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl or indanyl.

When the group R₁ is a substituted phenyl or fused bicylic carbocyclicgroup this refers to a group which is substituted by 1 to 3 groupsselected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino,C₁₋₆ alkanoylamino, ureido, alkylsulphonylamino, hydroxy,trifluoromethyl, trifluoromethoxy, nitro, cyano, SO₂ R₂ or COR₂ whereinR₂ represents hydroxy, methoxy, amino, alkylamino or dialkylamino.

When A is an optionally substituted C₁₋₄ alkylene chain this may be forexample methylene, ethylene, propylene, butylene or CH₂ CO. When A isthe chain (CH₂)_(p) Y (CH₂)_(q) this may be for example CH₂ OCH₂, CH₂NR₃ CH₂, CH₂ NH, NHCO, CH₂ NCH₃, CH₂ CH₂ NH, or CH₂ O.

When R₃ is a nitrogen protecting group this may be for exampleoptionally substituted benzyl, alkoxycarbonyl group e.g.t-butoxycarbonyl, aralkyloxycarbonyl, trimethylsilyethoxymethyl orarylsulphonyl e.g. phenylsulphonyl.

A preferred class of compounds of formula (I) are those wherein m is 1or 2 and within this class those wherein R is at the 4 and/or 6 positionare particularly preferred.

Examples of suitable R groups include chloro-, bromo, iodo-, methyl orethyl. More preferably R is a chloro group.

The group R₃ is conveniently hydrogen or C1-4alkyl e.g. methyl.

Conveniently the chain A is a group selected from C₂₋₃ alkyleneoptionally substituted by the group ═O, e.g. --(CH₂)₂ --, --CH₂ CO-- or--(CH₂)₃ -- or --(CH₂)_(p) Y(CH₂)_(q) -- wherein p is 1 or 2, q is zeroand Y is NH, NCH₃ or O e.g. --CH₂ NH-- --CH₂ NCH₃ -- --(CH₂)₂ NH-- or--CH₂ O or p is zero, Y is NH, q is 1 or 2and the group (CH₂)_(q) issubstituted by the group ═O e.g. --NHCO--

A preferred class of compounds of formula (I) include these wherein A isa chain selected from --(CH₂)₂ --, --(CH₂)₃ --, --CH₂ CO--, --CH₂ NH--,--CH₂ NCH₃, -- --CH₂ O-- or NHCO. Within this class those compoundswherein A is (CH₂)₂ -- or more particularly --CH₂ NH-- are especiallypreferred.

Conveniently the group R₁ is a group selected from optionallysubstituted phenyl, naphthyl e.g. 1-naphthyl, pyridyl e.g. 2-pyridyl,quinolinyl e.g. 2-quinolinyl, cyclohexyl or adamantyl e.g. 2-adamantyl.

When R₁ is an optionally substituted phenyl group this is convenientlyphenyl or phenyl substituted by amino, acetylamino,methanesulphonylamino or ureido which substituent is in the meta or morepreferably the para position.

A further preferred class of compounds of formula (I) are those whereinR₁ represents phenyl, or phenyl substituted by amino, acetylamino,methanesulphonylamino or ureido. Within this class those wherein R₁ isphenyl are particularly preferred.

Compounds wherein R₁ is optionally substituted phenyl, or 1-naphthylrepresent yet a further preferred class of compounds of formula (I).

Compounds of formula (I) in the exocyclic double bond is in the trans(E) configuration represent yet a further preferred class of compoundsof the invention.

A preferred group of compounds of formula (I) are those wherein m is 2and R is chlorine in the 4 and 6 positions, A is a chain selected from--(CH₂)₂ --, --(CH₂ )₃ --, --CH₂ CO--, --CH₂ NH--, --CH₂ NCH₃ --, groupselected from optionally substituted phenyl.

A further preferred group of compounds of formula (I) are those whereinm is 2 and R is chlorine in the 4 and 6 positions, A is CH₂ NH and R₁ isoptionally substituted phenyl, 2-pyridyl, 2-quinolinyl, 1 naphthyl,cyclohexyl or 2-adamantyl. Within this group particularly preferredcompounds are the trans (E) isomers thereof. More particularly thecompounds wherein R₁ is optionally substituted phenyl e.g. phenyl orphenyl substituted by amino, are especially preferred.

A particularly preferred compound of the invention is

(E)4,6-dichloro-3-(5-oxo-1-phenyl-pyrazolidin-4-ylidenemethyl)-1H-indole-2-carboxylicacid and physiologically acceptable salts thereof e.g. sodium orpotassium salts or metabolically labile esters thereof.

Further preferred compounds include (E)-4,6-dichloro-3-(2-oxo-1phenyl-pyrrolidinyl-3-ylidenemethyl)-1H-indole-2-carboxylic acid;

(E)4,6-dichloro-3-(2-oxo-1-phenyl-piperidin-3-ylidenemethyl)-1H-indole-2-carboxylicacid;

(E) 4,6-dichloro-3-(5-oxo-1-(4-aminophenyl))pyrazolidin-4-ylidenemetheyl!-1H-indole-2-carboxylicacid;

(Z)4,6-Dichloro-3-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2carboxylicacid;

(E)4,6-Dichloro-3-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2carboxylicacid;

4,6-Dichloro-3-5-oxo-1-(4-acetylamino-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid;

4,6-Dichloro-3-5-oxo-1-(4-ureido-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid;

4,6 -Dichloro-3-1-(4-methylsulfamidophenyl)-5-oxo-pyrazolidin-4-ylidenemethyl-1H-indole-2-carboxylicacid;

4,6-Dichloro-3-(3-oxo-2-phenyl-isoxazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid;

(E) 4,6-dichloro-3-(5-oxo-1-(3-aminophenyl))pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid;

(E)4,6-dichloro-3-(2,5-dioxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylicacid;

(E) 4,6-dichloro-3-(5-oxo-1-(1-naphthyl)pyrazolidin-4-ylidenemethyl!-1H-indole-carboxylicacid;

and physiologically acceptable salts thereof e.g. sodium or potassiumsalts or metabolically labile esters thereof.

The compounds of formula (I) and or physiologically acceptable saltsthereof are excitatory amino acid antagonists. More particularly theyare potent antagonists at the strychnine insensitive glycine bindingsite associated with the NMDA receptor complex. As such they are potentantagonists of the NMDA receptor complex. Moreover the compounds of theinvention exhibit an advantageous profile of activity including goodbioavailibility. These compounds are therefore useful in the treatmentor prevention of neurotoxic damage or neurodegenerative diseases. Thusthe compounds are useful for the treatment of neurotoxic injury whichfollows cerebral stroke, thromboembolic stroke, hemorrhagic stroke,cerebral ischemia, cerebral vasospam, hypoglycemia, anaesia, hypoxia,anoxia, perinatal asphyxia cardiac arrest. The compounds are useful inthe treatment of chronic neurodegenerative diseases such as;Huntingdon's disease, Alhzeimer's senile dementia, amyotrophic lateralsclerosis, Glutaric Acidaemia type, multi-infarct dementia, statusepilecticus, contusive injuries (e.g. spinal cord injury and headinjury), viral infection induced neurodengeration, (e.g. AIDS.encephalopaties), Down syndrome, epilepsy, schizophrenia, depression,anxiety, pain, neurogenic bladder, irritative bladder disturbances, drugdependency, icluding withdrawal symptoms from alcohol, cocaine, opiates,nicotine, benzodiazepine, and emesis.

The potent and selective action of the compound of the invention at thestrychnine insensitive glycine binding site present on the NMDA receptorcomplex may be readily determined using conventional test procedures.Thus the ability to bind at the strychnine insensitive glycine bindingsite was determined using the procedure of Kishimoto H et al. JNeurochem 1981, 37 1015-1024. The selectivity of the action of compoundsof the invention for the strychnine insensitive glycine site wasconfirmed in studies at other ionotropic known excitatory amino acidreceptors. Thus compound of the invention were found to show little orno affinity for the kainic acid (kainate) receptor,a-amino-3-hydroxy-5-methyl-4-isoxazole- proprionic acid (AMPA) receptoror at the NMDA binding site.

Compounds of the invention have also been found to inhibit NMDA inducedconvulsions in mice using the procedure Chiamulera C et al.Psychopharmacology (1990)102, 551-552.

The neuroprotective activity of compounds of the invention may bedemonstrated in the middle cerebral artery occlusion preparation inmice, using the procedure described by Chiamulera C et al. EuropeanJournal of Pharmacology 216 (1992) 335-336.

The invention therefore provides for the use of a compound of formula(I) and or physiologically acceptable salt or metabolically labile esterthereof for use in therapy and in particular use as medicine forantagonising the effects of excitatory amino acids upon the NMDAreceptor complex.

The invention also provides for the use of a compound of formula (I)and/or a physiologically acceptable salt or metabolically labile esterthereof for the manufacture of a medicament for antagonising the effectsof excitatory amino acids upon the NMDA receptor complex.

According to a further aspect the invention also provides for a methodfor antagonising the effects of excitatory amino acids upon the NMDAreceptor complex, comprising administering to a patient in need thereofan antagonistic amount of a compound of formula (I) and/or aphysiologically acceptable salt or metabolically labile ester thereof.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms.

It will further be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated the route of administration and the age and thecondition of the patient and will be ultimately at the discretion of theattendant physician. In general however doses employed for adult humantreatment will typically be in the range of 2 to 800 mg per day,dependent upon the route of administration.

Thus for parenteral administration a daily dose will typically be in therange 20-100 mg preferably 60-80 mg per day. For oral administration adaily dose will typically be within the range 200-800 mg e.g. 400-600 mgper day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or metabilcially labile ester thereof together with one or morepharmaceutically acceptable carriers thereof and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be"acceptable" in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The compositions of the invention include those in a form especiallyformulated for oral, buccal, parenteral, inhalation or insufflation,implant, or rectal administration. Parenteral administration ispreferred.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, accacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcrystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate,or wetting agents such as sodium lauryl sulphate. The tablets may becoated according to methods well known in the art. Oral liquidpreparations may be in the form of, for example, aqueous or oilysuspensions, solutions emulsions, syrups or elixirs, or may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; solubilizers such as surfactants for examplepolysorbates or other agents such as cyclodextrins; and preservatives,for example, methyl or propyl p- hydroxybenzoates or ascorbic acid. Thecompositions may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the invention may be formulated forparenteral administration by injection or continuous infusions.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form or constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellant, such as dichlorodifluoromethane, tirchlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant,such as dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, orfrom a nebuliser. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablecarrier such as lactose or starch. The powder composition may bepresented in unit dosage form in for example capsules or cartridges ofe.g. gelatin, or blister packs from which the powder may be administeredwith the aid of an inhaler or insulator.

The composition according to the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The compositions according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

Compounds of general formula (I) and salts thereof may be prepared bythe general methods outlined hereinafter. In the following description,the groups R, R₁, and R₂, m and A are as defined for the compounds offormula (I) unless otherwise stated.

Compounds of formula (I) wherein A has the meanings defined above withthe proviso that A is not --NHCO-- may be prepared by reaction of thealdehyde (II) (wherein R has the meanings defined above in formula (I)or is protected derivative thereof, R₄ is a carboxyl protecting groupand R₅ is a nitrogen protecting group). ##STR3## with the cyclic amide(Ill) (wherein R₁ and A have the meanings defined above in formula (I)or are protected derivatives thereof, with the proviso that A is not thegroup NHCO--) in the presence of a suitable base and if necessary ordesired subjecting the resulting compound to one or more of thefollowing operations.

a) removal of one or more protecting groups

b) isolation of the compound as a salt thereof

c) conversion of a compound of formula (I) or a salt thereof into ametabolically labile ester

d) conversion of a compound of formula (I) into a physiologicallyacceptable salt thereof.

In one embodiment of this process the aldehyde (II) is reacted with thecyclic amide (III) in the presence of a base such as t-butyl lithium,lithium diisopropylamide or lithium bis(trimethylsiyl)amide in ansolvent such as tetrahydrofuran. The reaction is initially carried outat a temperature around -78° but is n allowed to rise to 0° to 30° C.

The initial product of this reaction will depend upon the nature of theprotecting groups R₄ and R₅ since some of these may be cleaved under thereaction conditions. Examples of such groups include those wherein R₄ ismethyl or ethyl and or R₅ is alkoxycarbonyl e.g. t-butoxycarbonyl.

In the event that to reaction is carried out using an indole of formula(II) wherein the carboxyl protecting group R₄ is cleaved e.g. R₄ isethyl but the nitrogen protecting group R₅ is not, e.g.trimethylsilyl-ethoxymethyl the resultant carboxylic acid IV ##STR4##may be converted into a compound of formula (I) by removal of thenitrogen protecting group R₅. Alternatively the carboxylic acid (IV) maybe converted into the corresponding methyl ester (V) by reaction withdiazomethane. For this reaction trimethylsilyldiazomethane is aconvenient source of diazomethane and the reaction may be carried out ina suitable solvent such as a halohydrocarbon e.g. dichloromethane.##STR5##

The compound of formula (V) may be converted into a compound of formula(I) by removal of the nitrogen protecting group R₅ using conventionalmeans followed where desired or necessary by hydrolysis of the methylester.

In a second embodiment of the process the aldehyde (II) is reacted withthe cyclic amide (III) in the presence of a base such as butyl lithium,lithium diisopropylamide or lithium bis(trimethylsiyl)amide in anaprotic solvent such as tetrahydrofuran and at a temperature of around-78°. Reaction of the resultant secondary alcohol (VI) ##STR6## withhydrochloric acid and with heating in a solvent such as ethanol yieldsthe olefine (VII) ##STR7##

The ester (VII) may be converted into a compound of formula (I) byremoval of the carboxyl protecting group R₄ using conventionalprocedures.

In a modification of this process the secondary alcohol (VI) may beconverted into a reactive leaving group such as a sulphonate ester e.g.p-toluenesulphonate or methanesulphonate followed by treatment with anappropriate base such as lithiun diisopropylamide or sodium ethoxide.The resultant olefin may then be converted into a compound of theformula (I) by removal of the nitrogen protecting group R₅ and wherenecessary or desired the carboxyl protecting group R₄.

Suitable carboxyl protecting groups R₄ for use in these reactionsinclude allyl, alkyl, trichloroalkyl, trialkylsilylalkyl or arylmethylgroups such as benzyl, nitrobenzyl or trityl.

Suitable nitrogen protecting groups R₅ include alkoxycarbonyl e.g.t-butoxycarbonyl, arylsulphonyl e.g. phenylsulphonyl or2-trimethylsilylethoxymethyl.

The carboxyl protecting group R₄ may be removed by conventionalprocedures known for removing such groups. Thus compounds when R₄ is analkyl group, this may be removed by hydrolysis using an alkali metalhydroxide e.g. lithium hydroxide or sodium hydroxide in a solvent suchas an alkanol e.g. ethanol or isopropanol followed where desired ornecessary by that addition of a suitable acid e.g. hydrochloric acid ortrifluoroacetic acid to give the corresponding free carboxylic acid.

When R₄ is an allyl group this may be removed by treatment with an allylreceptor such as 5,5-dimethyl-1,3-cyclohexandione in the presence oftetrakis(triphenylphosphine) palladium.

Alternatively compounds wherein R₄ is an alkyl or benzyl group may beconverted into the corresponding carboxylic acid by reaction withtrimethylsilyl iodide in a solvent such as acetronitrile and withheating.

In any of in above reactions the nitrogen protecting group may beremoved by conventional procedures known for removing such groups, forexample by acid or base hydrolysis. Thus when R₅ is alkoxycarbonyl e.g.t-butoxycarbonyl may be removed by alkaline hydrolysis using for examplelithium hydroxide in a suitable solvent such as tetrahydrofuran or analkanol e.g. isopropanol or acid hydrolysis e.g. with formic acid,trifluoroacetic acid or hydrogen chloride in a solvent. When R₅ is atrimethylsilyethoxymethyl group this may be removed by acid hydrolysisusing hydrochloric acid or hydrogen chloride in a solvent such as analkanol e.g. ethanol.

Physiologically acceptable salts of compounds of formula (I) may beprepared by treating the corresponding acid with an appropriate base ina suitable solvent. For example alkali and alkaline metal salts may beprepared from an alkali or alkaline metal hydroxide, or thecorresponding carbonate or bicarbonate salts thereof. Alternativelyalkali or alkaline metal salts may be prepared by direct hydrolysis ofcarboxyl protected derivative of compound of formula (I) with theappropriate alkali or alkaline metal hydroxide.

When to compound of formula (I) contains a basic centre acid additionsalts may be prepared by reaction of the base with the appropriate acidand optionally in a solvent. Alternatively the acid addition salt may beobtained by direct hydrolysis of a carboxyl protected and or nitrogenprotected derivative thereof by reaction with the appropriate acid.

Metabolically labile esters of compounds of formula (I) may be preparedby esterification of the carboxylic acid group or a salt thereof or bytrans esterification using conventional procedures. Thus for exampleacyloxyalkyl esters may be prepared by reacting the free carboxylic acidor a salt thereof with the appropriate acyloxyalkyl halide in a suitablesolvent such as dimethylformamide. For the esterification of the freecarboxyl group this reaction is preferably carried out in the presenceof a quaternary ammonium halide such as tetrabutylammonium chloride orbenzyltriethylammonium chloride.

Aminoalkyl esters may be prepared by transesterification of acorresponding alkyl ester e.g. methyl or ethyl ester by reaction withthe corresponding aminoalkanol at an elevated temperature e.g. 50-150°.

For the reaction of the aldehyde (II) with the cyclic amide (Ill) it maybe necessary or desirable to carry out the reaction using protectedderivatives thereof. For example when one or both compounds contain aprimary or secondary amino group, or a hydroxyl or carboxyl group. Thesegroups may be protected in a conventional manner and the protectinggroups removed using conventional procedures as and when required.

Thus when the group R is amino or alkylamino, and or R₁ contains anamino or alkylamino substituent and or the group A contains a basic--NH-- group then it is desirable that each such basic nitrogen atom isprotected e.g. as a t-butoxycarbonyl derivative thereof. The nitrogenprotecting group may then be removed by conventional means; for examplereaction with trifluoroacetic acid in a suitable solvent e.g.dichloromethane, or hydrogen chloride in a solvent such as an alkanol.

Any hydroxy or carboxyl group may be conveniently protected as an esterthereof such as a t-butoxycarbonyl derivative of the hydroxy group or analkyl or allyl ester of the carboxyl group e.g. t-butyl or allyl esterthereof.

Compounds of formula (I) wherein A is the chain NHCO may be prepared byreaction of the aldehyde (II) or a protected derivative thereof with theglycine derivative (VIII) ##STR8## wherein R₁ is a group as defined informula (I) or a protected derivative thereof and R₆ and R₇independently represent C₁₋₄ alkyl. The reaction is carried out on thepresence of a base such as 1,8-diazabicyclo 5.4.0! undec-7-ene in anaprotic solvent such as ether e.g. tetrahydrofuran followed by removalof the protecting groups R₄ and R₅ together with any other protectinggroup present.

Compounds of formula (I) wherein A is the group CH₂ CO may be preparedby reaction of the aldehyde (II) with the phosphorane derivative (IX)wherein R₁ has the meanings defined in formula 1 or is a protectedderivative thereof. ##STR9##

The reaction is preferably carried out with heating in a suitablesolvent e.g. a hydrocarbon such as toluene, followed by removal of theprotecting groups R₄ and R₅, in a conventional manner.

Compounds of formula (I) wherein the exocyclic bond is in the cisconfiguration may be prepared isomerisation of the corresponding transisomer or a protected derivative thereof, followed by removal of anyprotecting group. The isomerisation reaction is conveniently carried outby irradiating a solution of the trans isomer in a suitable solvent suchas acetonitrile with UV light e.g. from a mercury lamp.

Compounds of formula (II) wherein R₄ is a carboxyl protecting group, andR₃ is a nitrogen protecting group may be prepared by treating thecorresponding indole (X). ##STR10## above with N- methylformanilide andphosphorous oxychloride in a solvent such as 1,2-dichloroethane.

The indoles of formula (X) are either known compounds or may be preparedby analogous methods to these described for the known compounds.

The cyclic amides of formula (III) are either known compounds or may beprepared using methods analogous to those described for known compoundse.g. Manhas and Jeng J. Org. Chem. 1967, 32 1246-1248, or Hargis D.C.and Shubkin R.L. Tetrahedron Letters vol 31 No. 21 pp. 2991-4 1990.

Thus compounds of formula (Ill) wherein A is the group (CH₂)_(p) NR₃wherein p is 1 or 2 and R₃ is a protecting group may be prepared byreaction of protected hydrazine R₁ NHR₃ with the haloacyl halide (XI).

    Z(Ch.sub.2).sub.1 COZ.sup.1                                (XI)

wherein Z and Z¹ are independently a halogen atoms e.g. chlorine bromineor iodine and r is 2 or 3. The reaction is conveniently carried out inthe presence of a base such as an alkali metal carbonate and in a polarsolvent such as N, N-dimethylformamide. A suitable protecting group R₃for use in this reaction is t-butyloxycarbonyl group. If required thisprotecting group may be removed by conventional means for example byreaction with trifluoroacetic acid in a solvent such as dichloromethane.The compound of formula (Ill) wherein A is the chain --(CH₂)_(p) NH--thus obtained may then be converted into a compound of formula (II)wherein A is the chain (CH₂)_(p) NF3 wherein R₆ is alkyl by aconventional alkylation reaction. For example by alkylation using theappropriate alkyl trifluoromethylsulphonate in a solvent such asdichloromethane.

Compounds of formula (III) wherein A is the group (CH₂)_(p) O where p is1 or 2 may be prepared by reaction of the hydroxylamine R₁ NHOH with thehalo acyl halide (XI) in the presence of a base such as potassiumcarbonate and in a polar solvent such as N,N-dimethylformamide.

The hydroxylamine R₁ NHOH may be prepared from the corresponding nitrocompound R₁ NO₂ in a conventional manner e. g. reaction with hydrazinein the presence of a 5% rhodium on carbon catalyst.

In order that the invention may be more fully understood the followingexamples are given by way of illustration only.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus ora Buchi capillary apparatus and are uncorrected. All temperature refersto ° C. Infrared spectra were mesured on a FT-IR instrument. ProtonMagnetic Resonance (¹ H-1NMR) spectra were recorded at 300 Mhz or400MHz, chemical shifts are reported in ppm downfield (d) from Me₄ Si, usedas internal standard, and are assigned as singlets (s), doublets (d),doublets of doublets (dd), triplets (t), quartets (q) or mutiplets (m).Colum chromathography was carrier out over silica gel (Merck AGDannstaadt, Germany). The following abbrevietions are used in textEA=ethyl acetate, CH=cyclohexane, DCM=dichloromethane.DMSO=dimethylsulphoxide, DBU=1,8diazabicyclo 5.4.0! undec-7-ene.

TIc refers to thin layer chromatography on silica plates. Solution weredried over anhydrous sodium sulphate. Tetrahydrofuran (THF) was freshlydistilled from K/benzophenone under nitrogen atmosphere; reagent gradecyclohexane and ethyl acetate were used wing futher purification. Allchromatography was done using silica gel, 230-400 mesh, (Merck). Yieldsare reported for isolated products which were pure by NMR and TIc.

INTERMEDIATE 1 Ethyl 4,6-dichloroindole-2-carboxylate

To a solution of ethyl pyruvate (2.05 ml), in absolute ethanol (38 ml),concentrated sulphuric acid (0.5 ml) was added slowly under vigorousstirring. The resulting mixture was stirred at 30° for 10 minutes, then3,5-dichlorophenylhydrazine hydrochloride (4 g) was added portionwise.The mixture was heated to reflux for 4 hours, cooled to 23°, poured intocold water (500 ml) and extracted with diethyl ether (3×300 ml). Theorganic layers were separated and dried. The solvent was evaporatedunder reduced pressure to give the2-(3,5-dichlorophenylhydrazone)propionic acid ethyl ester as yellowsolid (5 g; tlc DCM, R_(f=) 0.79, 0.47) in E and Z isomers mixture. Thesolid was added to polyphosphoric acid (20 g) under stirring and themixture was heated at 45° for 20 minutes to give a brown product whichwas crystallized by 95% ethanol (300 ml) to obtain the title compound asa yellow-brown solid (3.3 g;m.p. 180°; Tlc DCM, R_(f=) 0.54). IR(CDCl₃)Vmax(cm⁻¹)3440(NH), 1772-1709(C═O). ¹ H-NMR(CDCl₃) 9.00(s), 728(d),4.42(q), 1.42(t).

INTERMEDIATE 2 Ethyl 3-formyl-4,6-dichloroindol-2-carboxylate

A solution of N-methyl formanilide (5.19 g) and phosporos oxychloride(5.53 g) was stirred at 23° for 15 minutes. 1,2-Dichloroethane (60 ml)and intermediate 1 (6 g) were added and the resulting suspension wasstirred at 80° for 6 hours. The reaction mixture was poured into a 50%aqueous solution of sodium acetate (300 ml) to give, by filtration, thetitle compound as a yellow solid (4.1 g; tlc EA/CH:4/6, R_(f=) 0.4).IR(Nujol) Vmax(cm⁻¹) 1726 (C═O), 1663 (C═O), 1556 (C═C), 2725-2669 (CH).¹ H-NMR(DMSO) 13. 15(s), 10.60 (s), 7.54(d), 7.40(d), 4.43(q), 1.36 (t).

INTERMEDIATE 3

Ethyl3-formyl-1-(2-trimethylsilyl-ethoxymethyl)-4,6-dichloroindole-2-carboxylate

To a cooled solution of intermediate (2) (700 mg) in dry DMF (20 ml) at0° was added lithium bis-trimethylsilylamide (3.7 ml, 1M solution) inTHF. The mixture was stirred for 15 minutes at 0°, thentri-methylsilylethoxymethyl chloride (0.817 g) was added. After one hourthe resulting mixture was poured into water (25 ml) and extracted withethyl acetate (3×20 ml). The combined organic layers were dried andconcentrated under vacuum. The residue was purified by chromatography onsilica gel to afford the title compound (950 mg) as a pale yellow solid.

R_(f=) 0.3EtCH: 1.9.

INTERMEDIATE 4 Methyl (Z)4,6-dichloro-3-(2oxo-1-phenyl-pyrrolidin-3ylidenemethyl)-2-trimethylsilyl-ethoxymethyl)-1H-indole-2-carboxylate

1-phenyl-2-pyrrolidinone (426 mg) was dissolved in THF (10 ml), thesolution cooled to -78° and tert-butyllithium (1.80 ml, 1.6M solution inhexanes) slowly added; to the resulting solution, stirred at thistemperature for 1.5 h., intermediate 3 (1 g) dissolved in THF (10 ml)was added and stirring continued at =78° for 3 h. The reaction was thenallowed to warm to room temperature over 3 h and stirred for another 1.5h. The reaction was quenched with 20 ml of saturated NH₄ Cl solutiom,ethyl acetate (50 ml) was added and the orgaic phase separated andwasith 0.1M hydrochloric acid (2×20 ml), water (20 ml), brine (10 ml),and dried. The solvent was evaporated, the residue dissolved in 20 ml ofdichloromethane/methanol (4/1) and treated at room temperature withtrimethylsilyldiazomethane (1.70 ml, 2M solution in hexanes) for 30 min.Final purification by column chromatography (CH/EA 8/2) yielded thetitle compound (740 mg) as a white solid.

IR (nujol) Vmax (cm⁻¹) 1709 (C═O), 1684 (C═O). ¹ H NMR (CDCl3) 7.85 (t),7.80 (d), 7.50 (d), 7.40 (t), 720(d), 7.17 (t), 5.89 (s), 3.90 (s), 3.86(t), 3.53 (t), 264 (td), 0.88 (t), -0.05 (s).

INTERMEDIATE 5 Methyl(Z)4,6dichloro-3-(2-oxo-1-phenyl-piperidin-3ylidenemethyl)-1-(2-trimethvysilyl-ethoxvnethy)-1H-indole-2-carboxylate

N-phenylpiperidinone (370 mg) was dissolved in THF (10 ml), the solutioncooled to -78°, tert-butyllithium (1.30 ml, 1.6M solution in hexanes)was added and to the resulting mixture stirred at this temperature for1.5 h. intermediate 3 (800 mg) dissolved in THF (10 mw) was added and tnstirring continued at -78° for 3 h. The reaction was then allowed towarm to room temperature over 3 h and stirred for anoer 1.5 h. Thereaction was quenched with 20 ml of saturated NH₄ Cl solution, ethylacetate (50 ml) was added and the organic phase separated and washedwith 0.1M hydrochloric acid (2×20 ml), water (20 ml), brine (10 ml), anddried. The solvent was evaporated and the residue redissolved in 20 mlof dichloromethane/methanol (4/1) and treated at room temperature withtrimethylsilyldiazomethane (1.50 ml, 2M solution in hexanes) for 30 min.Final purification by column chromatography (CH/EA 7/3) yielded thetitle compound (700 mg) as a white solid.

IR (nujol) Vmax (cm⁻¹) 1713 (C═O), 1672 (C═O). ¹ H NMR (CDCl3) 8.09 (t),7.48 (d), 7.40 (m), 7.26 (tt), 7.18 (d), 5.90 (s), 3.89 (s), 3.76 (t),3.52 (m), 241 (td), 1.95 (m), 0.87 (t), 0.06 (s).

INTERMEDIATE 6 1-tert-butoxycarbonyl-2-phenyl hydrazine

Di tert-butyl dicarbonate (5.6 g) was added to a solution of phenylhydrazine (2.5 ml) in tetrahydrofuran (50 ml ). The solution was stirredat 25° for 2 hrs then concentrated in vacuo affording the crude titlecompound. (5.44 g) TIc EA/CH (1/2), R_(f=) 0.8

I.R.(cm⁻¹):1724(C═O), 1605(C═C)

INTERMEDIATE 7 1-tert-butoxycarbonyl-2-phenyl-pyrazolidin-3-one

To a solution of intermediate 6 (5.4 g) in dry dimethylformamide (50 ml)was added potassium carbonate (6.9 g) and after 5 min. chloro propionylchloride (2.4 ml). The resulting mixture was stirred at 25° for 2 hrs,then diluted with diethyl ether (200 ml), washed with water (2×200 ml),dried and concentrated in vacuo. The crude compound obtained wascrystallized from ethyl acetate/n-hexane to give the title compound (5.9g). T.I.c. diethyl ether/petroleum ether (1/1), R_(f=) 0.4. mp.=150°.

INTERMEDIATE 8 Ethyl4,6-dichloro-3-formyl-1-tert-butoxycarbonyl-1H-indole-2carboxylate

To a suspension of 4,6-dichloro-3-formyl-1H-indole-2-carboxylic acidethyl ester (8 g) in dry tetrahydrofuran (100ml) we added di-tert-butyldicarbonate (7.3 g) and 4-dimethylaminopyridine (0.7 g). The reactionmixture was stirred at 25° for 2 hrs, then diluted with ethyl acetate(300 ml), washed with ammonium chloride (sat.) (200 ml), brine (200 ml),dried and concentrated in vacuo. The crude title compound wascrystallized from ethyl acetate (8.6 g). T.I.c. EA/CH (112), R_(f=) 0.8.mp.=141°.

INTERMEDIATE 9 1-tert-butoxycarbonyl-2-(4-nitrophenyl) hydrazine

Di tert-butyl dicarbonate (7.8 g) was added to a solution of phenylhydrazine (2. 5 ml) in tetrahydrofuran (100mi). The solution was stirredat 25° for 2 hrs then concentrated in vacuo affording the crude productwhich was crystallized from ethyl acetate/n-hexane (1/3) to give thetitle cormpound (6.99 g). T.I.c EA/CH (112), R_(f=) 0.85. mp=12°.

INTERMEDIATE 10 1-tert-butoxycarbonyl-2(4-aminophenyl) hydrazine

A solution of sodium hydrosulfite (20 g) and potassium carbonate (22 g)in water (200 ml) was added to a solution of intermediate 9 (6 g) inethanol (350 ml). The resulting mixture was stirred at 25° for 1 hr,then concentrated in vacuo and extracted with ethyl acetate (200 ml).The organic phase was washed with ammonium chloride (sat.) (2×200 ml),dried and concentrated in vacuo. The crude compound was purified bysilica gel column chromatograph using EA/CH (1/2) as eluant to give thetitle compound (3 g). T.I.c EA/CH (1/1), RF=0.2 mp.=128°.

INTERMEDIATE 11 1-tert-butoxycarbonyl-2-4(-tert-butoxycarbonylamino)phenyl!hydrazine

Di tert-butyl dicarbonate (3.33 g) was added to a solution ofintermediate 10 (341 g) in tetrahydrofuran (100 ml). The solution wasstirred at 25° for 15 hrs then concentrated in vacuo affording the crudetitle compound which was crystallized from ethyl acetate/n-hexane (4.4g). T.I.c. EA/CH (1/2), R_(f=) 0.90. mp.=155°.

INTERMEDIATE 12 1-tert-butoxycarbonyl-2(4-tert-butoxycarbonylamino!phenylidin3-one

To a solution of intermediate 11 (0.5 g) in dry dimethylformamide (5 ml)was added potassium carbonate (0.213 g) and after 15 min. chloropropionyl chloride (0.15 ml). The resulting mixture was stirred at 25°for 20 hrs then diluted with diethyl ether (50 ml). It was the washedwith water (50 m) and ammonium chloride (sat.) (50 ml). After drying,the solution was concentrated in vacuo to give the crude compound whichwas crystallized from ethyl acetate/n-hexane (1/4) to give the titlecompound (0.252 g. ). T.I.c. EA/CH (1/1). R_(f=) 0.60. mp.=178°.

INTERMEDIATE 13 4,6Dichloroindole3-formyl-2-carboxylic acid

To a suspension of the intermediate (2) (7.0 g, ) in ethyl alcohol (250ml) lithium hydroxide (2.26 g) was added. The yellow solution was heatedat 50 for 8 hours then acidified with HCl till pH=2 . The precipitatewas collected by filtration to furnish the title compound as a whitesolid (6.29,). mp=235-240.

INTERMEDIATE 13a 4,6-Dichloroindole3-formyl-2-carboxylic acid tert-butylester

To a refluxing suspension of intermediate 13 (1.0 g,) in dry toluene (50ml) N, N-dimethylformamide di-tert-butyl acetal (4.38 g,) was slowlyadded. The heating continued for 30 minutes then the dark solution wascooled and washed with water, sodium bicarbonate solution and brine. Theorganic layer was dried and the solvent removed under reduced pressure.The residue was purified by flash chromatograph (CH/EA=8/2 R_(f) =0.33)to give the title compound as a white solid (470 mg).

IR (Nujol) ν_(max) (cm⁻¹) 3335 (N--H), 1724 (C═O) and 1663 (C═O).

INTERMEDIATE 144,6-Dichloroindole-3-formyl1-tertbutyloxycarbonyl-2-carboxylic acid-tert-butyl ester

To a solution of intemediate 13a (470 mg,) in dry THF (10 ml),4-dimethylaminopyridine (22 mg) and a solubon of di-tert butyldicarbonate (392 mg) in dry THF (5 ml) were added. The solution wasstirred for 30 minutes then the solvent removed under reduced pressure.The residue was purified by flash chromatography (CH/EA=9/1R_(f) =0.38)to give the title compound as a foam. (468 mg)

IR (Nujol) μ_(max) (cm⁻¹) 1765 (C═O), 1740(C═O) and 1688 (C═O).

INTERMEDIATE 15 N-(Phenylaminocarbonyl)-α-phosphonoglycine trimethylester

A solution of N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester(3 g.) in methanol (50 ml) was hydrogenated under a 1 atm. pressure for5 hrs in the presence of 5% palladium on carbon (0.55 g. ). The catalystwas filtered off on celite and the solution was evaporated under reducedpressure. The residue was dissolved in dichloromethane (15 ml), phenylisocyanate (1.1 ml) was added and the reaction mixture was stirred for15 hrs. The solvent was evaporated under reduced pressure and theresidue was triturated in diethyl ether (50 ml ) to give the titlecompound as a white powder (2.4 g m.p 144-146°

IR (Nujol) ν_(max) (cm⁻¹) 1745 (C═O), 1707(C═O)

INTERMEDIATE 16 (Z)4,6-Dichloroindole-3-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-indole-1,2-dicarboxylicacid 1,2di-tertbutyl ester)

To a solution of intermediate 15 (367 mg) in dry THF (8 ml), DBU (352mg.) was added dropwise. The solution was stirred at room temperaturefor 10 minutes, then a solution of intermediate 16(480 mg) in dry THF(10 ml) was slowly added. The mixture was stirred for 15 minutes,diluted with ethyl acetate (10 ml) and quenched with ammonium chloride.The organic layer was dried and the solvent evaporated under reducedpressure. The residue was purified by flash chromatography (CH/EA=85/15R_(f) =0.33) to give the title compound as a foam (284 mg).

IR (Nujol) ν_(max) (cm⁻¹) 1772 (C═O), 1726 (C═O) and 1678 (C═O).

INTERMEDIATE 17 4,6-Dichloroindole-3-formyl-2-carboxylic acid allylester

To a suspension of intermediate of intermediate 2 (3.0 g) in allylalcohol (100 ml) p-toluenesulfonic acid monohydrate (2.0 g) was added.The suspension was heated at 90° for 2.5 hours, then the solvent removedunder reduced pressure. The residue was dissolved in methylene chlorideswashed with a solution of Na₂ CO₃ (10%), water and purified by flashchromatography (CH/EA=7/3 R_(f) =0.34) to give the title compound as awhite solid (1.10 g).

IR (Nujol) ν_(max) (cm⁻¹) 1720 (C═O) and 1657 (C═O). ¹ H-NMR (DMSO)13.20 (bs), 1061 (s), 7.55 (d), 742 (d), 6.14-6.0 (r), 5.46 (dd), 5.33(dd) and 4.92 (d). m/z (FAB) 298 (MH).

INTERMEDIATE 184,6-Dichloroindole-1-tet-butyloxycarbonyl-3-formyl-2-carboxylic acidallyl ester

To a solution of intermediate 17 (1.10 g) in dry THF (40 ml),4-dimethylaminopyridine (49 mg) and a solution of di-tert-butyldicarbonate (886 mg) in dry THF (10 ml), were added. The solution wasstirred for 1 hours then the solvent removed under reduced pressure. Theresidue was purified by flash chromatography (CH/EA=9/1 R_(f) =0.37) togive the title compound as a white solid (853 mg; mp.=106.9-107.7).

IR (Nujol) ν_(max) (cm⁻¹) 1757-1744 (C═O) and 1682 (C═O).

INTERMEDIATE 19 (E) 4,6Dichloro-3-(2,5dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-indole1,2-dicarboxylicacid 2-allyl ester 1-tertbutyl ester

To a solution or intermediate 15 (590 mg) in dry THF (10 ml) DBU (566mg) was added dropwise. The solution was stirred at room temperature for10 minutes, then a solution of intermediate 18 (740 mg) in dry THF (15ml) was slowly added. The mixture was stirred for 15 minutes, dilutedwith ethyl acetate (10 ml) and quenched with ammonium chloride. Theorganic layer was dried and the solvent evaporated under reducedpressure. The residue was purified by flash chromatography (CH/EA=7/3R_(f) =0.27) to give the tile compound as a foam (369 mg).

IR (Nujol) ν_(max) (cm⁻¹) 3331 (N--H), 1730 (C═O), 1673 (C═O) and1533(C═C).

INTERMEDIATE 20 E3-(1-tert-butoxycarbonyl-3-oxo-2-phenyl)pyrazolidin-4-ylidenemethyl-!4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2-carboxylic acidtert butyl ester

To a solution of Example 15 (0.7 g) in dry tetrahydrofuran (50 ml) wereadded di-tert-butyl-di-carbonate (33 g) and 4-dimethylaminopyridine(0.03 g). The solution was stirred at 25° for 30 min., then diluted withdiethyl ether (200 ml), washed with ammonium chloride (sat.) (200 ml),brine (200 ml), dried and concentrated in vacuo. The crude titlecompound was purified by silica gel column chromatography using diethylether and petrol (2/8) as eluant to give the title compound (0.54 g).T.I.c. diethyl ether/petrol (5/25), R_(f) =0.45.

1H-NMR(CDCl₃): 1.27(s,9H), 1.52(s,9H), 1.67(s,9H), 4.65(d,2H),7.18(t,1H, 7.27(d,1H), 7.39(m,2H), 7.65(m,1H), 7.66(m,2H), 8.04(d,1H).

INTERMEDIATE 21 (Z)3-(1-tert-butoxycarbonyl-3-oxo-2-phenyl)pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2-carboxylic acidtert butyl ester

A solution of intermediate 20 (0.53 ) in acetonitrile (30 ml) wasirradiated using a 400 Watt mercury lamp for 45 mins. The solution wasconcentrated in vacuo to give a mixture of the two isomers that wereseparated by silica gel column chromatography using ethylacetate/cyclohexane (5/95) as eluant to obtain the title compound 6(0.13 g). T.I.c EA/CH (5/25), R_(f) =0.85.

1H-NMR(CDCl₃): 1.27(s,9H), 1.51(s,9H), 1.65(s,9H), 4.86(m,2H), 7.07(m,1H), 7.09(m,1H), 720(d,1H), 7.28(m,2H), 7.57(m,2H), 7.97(d,1H).

INTERMEDIATE 22

b 1-tert-butoxycarbonyl-2-(4-methylsulfamidophenyl)hydrazine

To a solution of intermediate 10 (0.2 g) in tetrahydrofuran (5 ml) undernitrogen at 0° C. was added pyridine(0.045 ml). After 5 minutemethanesulfonyl chloride((0.045 ml) was added dropwise to the stirredsolution. The reaction mixture was allowed to warm up to roomtemperature. After 1 hour saturated ammonium chloride solution(20 ml)was added and the reaction mixture extracted with ethyl acetate (3×10ml) and the combined extracts dried. The solvent was removed bydistillation under reduced pressure and the product purified by flashcolumn chromatography over silica gel CH/EA yielding the title compoundas a yellow solid (0.140 g).

I.R. (cm-1, Nujol):3302(NH), 1709(C═O), 1600(C═C), 1323-1151(SO2).

INTERMEDIATE 231-tert-butoxycarbonyl-2-(4-methylsulfamidophenyl)-pyrazolidin-3-one

To a stirred solution of intermediate 22 (0.6 g) in drydimethylformamide (15 ml) under nitrogen at 0° was added pyridine(0.23ml). Chloro propionyl chloride (0.2 ml) was then added dropwise to thesolution. The mixture reaction was stirred at 25° C. for 2 hrs dilutedwith ethyl acetate (50 ml), and then washed with water(50 ml) andsaturated ammonium chloride solution(50 ml). The organic solution wasdried and then concentrated in vacuo to give crude1-tert-butoxycarbonyl-(4-methylsulfamidophenyl)-2-(3-chloropropionyl)hydrazineas a yellow oil. This was dissolved in dimethylformamide(5 ml) undernitrogen and at 25° anhydrous potassium carbonate (0.450 g) was added.The resulting mixture was stirred for 1 hr then diluted with saturatedammonium chloride solution (50 ml). The aqueous solution was extractedwith ethyl acetate (3×50) and the combined organic phases were dried andconcentrated in vacuo. The crude residue was purified by silica gelflash column chromatography eluting with diethyl ether to give the titlecompound (0.25 g).

1H-NMR(DMSO); 1.28(s,9H), 2.73(t,2H) 2.93(s,3H), 4.06(t2H), 7.19(d,2H),7.42(d,2H1), 9.66(s,1H). I.R (cm-1, Nujol):3252-3202(NH), 1693(C═O),1600(C═C), 1310-1151(SO2).

INTERMEDIATE 24 2-phenyl-pyrazolidin-3-one

Intermediate 7 (4.6 g) was dissolved in dry dichloromethane (10 ml) andtrifluoroacetic acid (10 ml). The resulting solution was stirred. at 25°for 1 hr then concentrated in vacuo. The residue was dissolved in ethylacetate (100 ml), washed with sodium bicarbonate (sat) (2×100 ml), brine(100 ml), dried and concentrated in vacuo to give the crude titlecompound (2.6 g). T.I.c. CH/EA (1/1), R_(f) =0.30

1H-NMR (CDCl₃): 278(t,2H), 3.52(q,2H), 4.75(t,1H), 7.12(tt,1H),7.36(t,2H), 7.85(d,2H). l.R (cm-1): 3238(NH), 1674(C═O)

INTERMEDIATE 25

1-methyl-2-phenyl-pyrazolidin-one

To a solution of intermediate 24 (1.43 g) in dimethylformammide (20 ml)was added dropwise and at -20° methyl trifluoromethanesulfonate ((1.4ml). The reaction mid was allowed to warm-up to 25° and after 3 hrs wasdiluted with diethyl ether (200 ml), washed with ammonium chloride (sat)(200 ml), water (200 ml), dried and concentrated in vacuo. The crudecompound was purified by silica gel column chromatography using ethylacetate/cyclohexane (3/7) as eluant to give the title compound (0.4 g).T.I.c. CH/EA (1/1). R_(f) =0.42.

I.R (cm-1): 1697 (C═O).

INTERMEDIATE 26

N-(3-chloropropionyl)-N-phenylhydroxylamine

To a suspension of rhodium on carbon 5% (0.13 g) in dry tetrahydrofuran(23 ml) was added nitrobenzene (5 g). The mixture was cooled at 0° andhydrazine hydrate (2 g) was added dropwise. The temperature of themixture is maintained at 25-30° throughout the addition; after thereaction was stirred at 25° for 2 hrs then filtered and the catalystwashed with a little tetrahydrofuran. The solution was concentrated invacuum and the residue was dissolved in dimethylformamide (30 ml) andcooled at -50°, then potassium carbonate (5.6 g) and, after 10 min.,chloro propionyl chloride (3.8 ml) were added. The reaction mixture wasstirred at 25° for 1 hr then diluted with diethyl ether (150 ml), washedwith water (2×200 ml), dried and concentrated in vacuo. The residue waspurified by crystallization using ethyl acetate/cyclohexane to give thetitle compound as a solid (4 g). T.I.c CH/EA 1/2 R_(f) =0.3.

1H-NMR (CDCl₃): 2.7(bs,2H), 3.8(t,2H), 7.5(bm,5H). I.R (cm-1):1645(C═O), 1626(C═C).

INTERMEDIATE 27

3-oxo-2-phenyl-isoxazolidine

To a solution of intermediate 26 (3.35 g) in acetone (150 ml) was addedpotassium carbonate (2.3 g). The reaction mixture was stirred at 25° for6 hrs then concentrated in vacuo. The residue was triturated with ethylacetate, filtered and concentrated in vacuo to obtain the crude titlecompound as an oil (2.5 g). T.I.c. CH/EA 1/2 , R_(f) =0.3.

1H-NMR (CDCl₃): 3.0(t,2H), 4.52(t,2H), 7.14(tt,1H), 7.37(m,2H),7.69(m,2H). I.R (cm-1): 1697(C═O).

INTERMEDIATE 28

1-tert-butoxycarbonyl-2-(3-nitrophenyl)hydrazine

To a solution of 3-nitrophenyl hydrazine (6 g) in dioxane (60 ml) andwater (30 ml) were added sodium hydroxide 1M (30 ml) and di tert-butyldicarbonate (7.6 g). The solution was stirred at 25° for 2 hrs thenconcentrated in vacuo; diluted in ethyl acetate (200 ml), washed withammonium chloride (sat.) (2×200 ml), brine (2×200 ml), dried andconcentrated in vacuo to give the crude intermediate which was purifiedby trituration with ethyl acetate/cyclohexane (19/29) to obtain thetitle compound (4.3 g,). T.I.c. EA/CH (1/1), R_(f) =0.85 m.p=105°.

INTERMEDIATE 28a1-tert-butoxycarbonyl-2-(3-tert-butoxycarbonylamino)phenylhydrazine

To a solution of intermediate 28 (3.64 g) in ethanol (70 ml) were addediron powder (7.0 g) and calcium chloride (0.71 g). The reaction mixturewas heated at 70° C. for 20 hrs then filtered over silica gel washingwith ethyl acetate. The solution was dried and concentrated in vacuo toafford the 1-tert-butoxycarbonyl-2-(3-aminophenyl)hydrazine (3.0 g) thatwas dissolved in dry tetrahydrofuran (100 ml) anddi-tertbutyl-di-carbonate (3.68 g) was added. The reaction mixture wasstirred at 25° for 20 hrs than concentrated in vacuo. The product waspurified by trituration with ethyl acetate to give the title compound(3.73 g). T.I.c. EA/CH (1/1); R_(f) =0.7.

I.R (cm-1): 3329 and 3294(NH), 1715 and 1697(C═O), 1610(C═C).

INTERMEDIATE 29

1-tert-butoxycarbonyl-2-(3-tert-butoxycarbonylamino)phenyl!pyrazolidin-3-one

To a solution of intermediate 28a (0.316 g) in dry dimethylformamide(4.0 ml) was added potassium carbonate (0.142 g) and after 15 min.chloro propionyl chloride (0.098 ml). The resulting mixture was stirredat 25° for 3 hrs then diluted with diethyl ether (50 ml),washed withammonium chloride (sat) (50 ml) and brine (50 ml). After drying, thesolution was concentrated in vacuo and the residue (0.4 g) was dissolvedin dimethylformamide (4.78 ml). Potassium carbonate (0.139 g) was addedand the mixture stirred at 25° for 3 hrs. The reaction mixture was thendiluted with diethyl ether (50 ml) washed with ammonium chloride (sat.)(50 ml) and brine (50 ml). After drying, the solution was concentratedin vacuo to give the crude compound (0.4 g) which was purified by silicagel column chromatography using ethyl acetate/cyclohexane (1/3) aseluant to obtain the title compound (0.27 g. ). T.I.c. EA/CH (1/3),R_(f=) 0.25. m.p.=129°.

INTERMEDIATE 30 and intermediate 31 (E)3- (1-tert-butoxycarbonyl-2-(3tert-butoxycarbonylamino)phenyl!-3-oxo)pyrazolidin4-ylidenemethyl!4,6-dichloro-1H-indole-2-carboxylic acid tert butyl ester (30)(E)3- (1-tert-butoxycarbonyl-2-(3-tert-butoxycarbonylamino)phenyl!3-oxo)pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2 -carboxylic acidtert butyl ester (31)

To a solution of intermediate 4 (0.196 g) in dry tetrahydrofuran (5 ml)was added dropwise, at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (0.564 ml). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution of4,6-dichloro-3-formyl-1- -N-tert-butoxycarbonyl!-1H-indole-2-carboxylicacid tert butyl ester (0.18 g) in dry tetrahydrofuran (4 ml) was added.The solution was maintained at -40° for 30 min. then warmed up to 0° C.for 2 hrs. The solution was diluted with ethyl acetate (50 ml) andwashed ammonium chloride (50 ml), brine (50 ml), dried and concentratedin vacuo. The crude compound was purified by silica gel columnchromatography using ethyl acetate/cyclohexane (3/97) as eluant to givethe Intermediate 38 (0.05 g), T.I.c. EA/CH (1/2), R_(f) =0.5 ! andIntermediate 39 (0.04 g), T.I.c. EA/CH

INTERMEDIATE 30

1H-NMR (DMSO): 1.21(s,9H), 1.45(s,9H), 1.51(s,9H), 4.49(d,2H), 7.17(m,1H), 7.3-7.2(m 2H), 7.30(d,1H), 7.50(d,1H), 7.74(t,1H), 7.82(t,1H),9.43(1H), 12.4(bs,1H). I.R (cm-1): 3346(NH), 1728 and 1684(C═O). ms(m/z): 773, 758, 673, 561.

INTERMEDIATE 31

1H-NMR (DMSO): 1.23(s,9H), 1.45(s,18H), 1.61(s,9H), 4.57(d,2H),7.18(m,1H), 7.25(m,2H), 7.49(t,1H), 7.57(d,1H), 7.82(bs,1H), 7.94(d,1H),9.44(s, 1H) I.R. (cm-1): 3341(NH), 1726(C═O). ms (m/z): 773, 242.

INTERMEDIATE 32 (E)4,6-dichloro-3-(2,5-dioxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-indole-1,2-dicarboxylicacid di-tert-butyl ester

To a solution of intermediate 14 (440 mg) in dry toluene (20 ml) theN-phenyltriphenylphosphoranylidene succinimide (472 mg) was added. Thesolution was heated at 70° for 21 hours then more succinimide (236 mg)was added and the heating continued for 10 hours. The solvent wasremoved under reduced pressure and the residue purified by flashchromatography (CH/EA=8/2 R_(f) =0.38) to give the title compound as awhite solid (309 mg).

IR (Nujol) ν_(max) (cm-1) 1750 (C═O).

INTERMEDIATE 331-tert-butoxycarbonyl-3-oxo-2-phenyl-tetrahydro-pyridazine

To a solution of Intermediate 6 (1 g) in dry dimethylformamide (10 ml)was added pyridine (0.78 ml) and 4-bromobutyryl chloride (0.83 ml),under nitrogen at 25°, and the reaction mixture was stirred for 15 hrs.The solution was diluted with diethyl ether (80 ml) and washed withbrine (2×80 ml). After drying, the organic solution was concentrated invacuo to give a yellow oil (1.7 g). To a solution of this oil (2.25 g)in dimethyformamide (15 ml), under nitrogen at 25°, anhydrous potassiumcarbonate (1.7 g) was added and the resulting mixture, was stirred for 3hr. The solution was-diluted with diethyl ether (100 ml), washed withbrine (2×80 ml), dried and concent purified by silica gel flash columnchromatography using cyclohexane/ethyl acetate (8/2) as eluant to givetitle compound (1.4 g) as a white powder. T.I.c. EA/CH (1/1) R_(f) =0.60

INTERMEDIATE 34 2-quinolinylhydrazine

To a solution of 2-chloroquinoline (15 g) in ethanol (150 ml) was addedhydrazine hydrate (40 ml) the resulting solution was heated at refluxfor 6 hrs then diluted with water (400 ml) and extracted with diethylether (3×200 ml). The collected organic phase was washed with brine (300ml), dried and concentrated under vacuum to afforg the title compound asa solid (13 g)

1H-NMR(DMSO): 4.29(s,2H), 6.83(d,1H), 7.15(m,1H), 7.47(m,1H), 7.52(d,1H), 7.62(dd,1H), 7.86(d,1H), 8.05(s,1H).

INTERMEDIATE 35 1-tert-butoxycarbonyl-2-(2-quinolinyl)hydrazine

To a solution of intermediate 34 (13 g) in tetrahydrofuran (150 ml) wasadded di-tert-butyl dicarbonate (18 g). The solution was stirred at 25°for 1 hr then concentrated in vacuo and triturated with ethylacetate/n-hexane to obtain the title compound (19 g). T.I.c. EA/CH(1/2), R_(f=) 0.3. m.p. =148°-150°.

INTERMEDIATE 36 1-tert-butoxycarbonyl-2-3-chloronpropanoyl-2-quinolinyl-hydrazine

To a solution of intermediate 35 (5 g) in tetrahydrofuran (60 ml) wasadded dropwise and at 0° a solution of chloro propionyl chloride (0.92ml) in tetrahydrofuran (40 ml). The resulting heterogeneous solution wasstirred at 0° for 30 min., filtered and concentrated in vacuo to givethe title compound (2.7 g) as a foam. T.I.c. EA/CH (1/1), R_(f=) 0.8.

INTERMEDIATE 37 1-tert-butoxycarbonyl-2-(2-quinolinyl)-pyrazolidin-3-one

Potassium carbonate (1.3 g) was added to a solution of Intermediate 36(2.7 g) dissolved in dimethylformamide (30 ml). The reaction mixture wasstirred at 25° for 2 hrs then diluted with-diethyl ether (100 ml),washed with water (100 ml), dried and concentrated in vacuo. The crudeproduct was purified by silica gel column chromatography using ethylacetate/cyclohexane (2/8) as eluant to obtain the title compound (0.84g) as a foam. T.I.c. EA/CH (1i1); R_(f=) 0.6. m.p.=112°.

INTERMEDIATE 38 (E)3- 1-tert-butoxycarbonyl-2-(2quinolinyl)-3-oxo-!pyrazolidin-4-ylidenemethyl!4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2-carboxylic acidtert butyl ester

A solution of intermediate 37 (0.1 7 g) in dry tetrahydrofuran (10 ml)was added dropwise, at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (0.62 ml). The reactionmixture was allowed to warm up to =20° in 30 min., then a solution of4,6-dichloro-formyl-1- N-tert-butoxycarbonyl!-1H-indole-2-carboxylicacid tert butyl ester (0.2 g) in dry tetrahydrofuran (10 ml) was added.The solution was maintained at -20° for 30 min. then warmed up to 25° C.for 2 hrs. The solution was diluted with hydrochloric acid (50 ml),extracted with diethyl ether (3×40 ml) and the collected organic phasedried and concentrated in vacuo. The crude compound was purified bysilica gel column chromatography using EA/CH (1/9) as eluant to give thetitle compound (0.125 g), T.I.c. EA/CH (1/2), R_(f) =7 m.p.=48°51°.

INTERMEDIATE 39 1-tert-butoxycarbonyl-2-(2-pyridyl)hydrazine

2-chloropyridine (23 g) was added to hydrazine hydrate (110 ml). Theresulting solution was heated at reflux for 6 hrs then extracted withdiethyl ether (2×100 ml).

The aqueous phase was concentrated in vacuo, diluted with water (40 ml)then potassium hydroxide (2 g) was added and the solution extracted withdiethyl ether (100 ml). The collected organic phase was dried andconcentrated in vacuo to afforg the crude 2-pyridin-hydrazineintermediate as a solid (13 g) that was dissolved in tetrahydrofuran(200 ml) and di-tert-butyl dicarbonate (26 g) was added. The solutionwas stirred at 25° for 1 hr then concentrated in vacuo and trituratedfrom ethyl acetate/n-hexane to obtain the title compound (16 g). T.I.c.EA/CH (2/1), R_(f=) 0.54. m.p.=91° C.

INTERMEDIATE 401-tert-butoxycarbonyl-2(3-chloropropanoyl-2-pyridyl)-hydrazine

To a solution of intermediate 39 (49) in tetrahydrofuran (60 ml) wasadded dropwise and at 0° a solution of chloro propionyl chloride (0.92ml) in tetrahydrofuran (40 ml). The resulting heterogeneous mixture wasstirred at 0° for 30 min., filtered and concentrated in vacuo to givethe crude title compound as a foam T.I.c EA/CH (1/1), R_(f=) 08.

INTERMEDIATE 41 1 -tert-butoxycarbonyl2(2-pyridyl)-pyrazolidin3-one

Potassium carbonate (1.3 g) was added to a solution of Intermediate40dissolved in dimethylformamide (30 ml) The reaction mixture was stirredat 25° for 2 hr diluted with diethyl ether (100 ml), washed with water(100 ml), dried and concentrated in vacuo. The crude product waspurified by silica gel column chromatography using ethylacetate/cyclohexane (2/8) as eluant to obtain the title compound (0.87g)as a foam T.I.c. EA/CH (1/1); R_(f=) 0.65.

1H-NMR(CDCl₃): 1.50(s, 9H), 2.59(t, 2H), 4.27(m, 2H), 6.81(dd, 1H),6.96(m, 1H), 7.63(m, 1H). 8.33(m, 1H).

INTERMEDIATE 42 (E)3-1-tert-butoxycarbonyl-2-(2-pyridyl)-3-oxo!pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2-carboxylic acidtert butyl ester

To a solution of intermediate 41 (0.361 g) in dry tetrahydrofuran (10ml) was added dropwise, at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (1.6 ml). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution of4,6-dichloro-3-formyl-1 N-tert-butoxycarbonyl!-1H-indole-2-carboxylicacid tert butyl ester (0.2 g) in dry tetrahydrofuran (10 ml) was added.The solution was maintained at -20° for 30 min. then warmed up to 25°for 2 hrs. The solution was diluted with hydrochloric acid (50 ml),extracted with ethyl acetate (2×50 ml) and the collected organic phaseand concentrated in vacuo. The crude compound was purified by silica gelcolumn chromatography using ethyl acetate/cyclohexane (2/8) as eluent togive the title compound (0.06 g) as a foam. T.I.c. EA/CH (1/1), R_(f=)0.85.

1H-NMR (CDCl₃): 1.38(s, 9H), 1.53(s, 9H), 1.64(s, 9H), 4.67(d, 2H),6.19(ddd, 1H), 6.78(1H), 7.18(d, 1H), 7.58(ddd, 1H), 7.70(t, 1H),7.98(d, 1H), 8.23(bm, 1H).

INTERMEDIATE 43 1-naphthyl hydrazine

Sodium nitrite (4.8 g) in water (20 ml) was added over 15 minutes to astirred ice-cold suspension of 1-naphthylamine (9.58 g) in 6Mhydrochloric acid (80 ml). After an additional 30 minutes in the icebath, stannous chloride (44.5 9) in 6M hydrochloric acid (80 ml) wasadded slowly and the resulting suspension was stirred at O0 for 3 hr.The resulting solid was filtered off and dissolved in a mixture of 40%potassium hydroxide solution (100 ml) and ethyl acetate (150 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (3×100 ml). The combined organic extracts were dried andconcentrated under reduced pressure to afford the title compound as apurple solid (10.58 g R_(f=) 0.1 in EA/CH (1/4)).

I.R.(cm-1):3312-3474(NH and NH₂);1580-1610,(C═C)

INTERMEDIATE 44 1-tert-butoxycarbonyl-2-(1-naphthyl) hydrazine

Di tert-butyl dicarbonate (14.3 g) was added to a solution ofintermediate 43 (6.9 g) in tetrahydrofuran (350 ml). The solution wasstirred at 25° for 8 hrs then concentrated in vacuo affording the crudetitle compound which was purified by column chromatography(ethylacetate/cyclohexane. 1/4). to give the title compound a brownsolid (9 g) T.I.c. EA/CH (114), R_(f=) 0.45.; m.p.=109^(O)

INTERMEDIATE 45 1-tert-butoxycarbonyl-2-(1-naphthyl)pyrazolidin-3-one

To a solution of intermediate 44 (3 g) in dry dimethylformamide (45 ml)was added potassium carbonate (2.2 g) and after 5 min. chloro propionylchloride (1.5 ml). The resulting mixture was stirred at 25° for 2 hrs,then diluted with diethyl ether (200 ml), washed with water (2×100 ml),dried and concentrated in vacuo. The residue was crystallized fromdiethyl ether to give a white solid (1.5 g) This was dissolved indimethylformamide (17.9 ml) and potassium-carbonate (0.62 g) was added.The reaction mixture was stirred at 25° for 3 hrs then diluted withdiethyl ether (100 ml), washed with water (100 ml), dried andconcentrated in vacuo to give a product which was purified by silica gelcolumn chromatography using diethyl ether/cyclohexane (2/1) as eluant toobtain the title compound (1.09 g) as a pale yellow foam. T. I. c.diethyl ether/cyclohexane 2/1); R_(f=) 0.37.

INTERMEDIATE 46 tert-butyl adamantylidenecarbazate

A hexane solution containing 2-adamantanone (2 g) and tert-butylcarbazate (1.76) was heated to reflux for 3 hours. When the solutioncooled, the title compound crystallized and was filtered (3.28 g). M. p.175-177°.

INTERMEDIATE 47 1-tert-butoxycarbonyl-2-(2-adamantyl)hydrazine

A solution of intermediate 46 (2.13 g), Pd/C 20 % w/w catalyst (0.4 g)and 150 ml of absolute ethanol was placed in a pressure bottle on a Paarhydrogenation apparatus. Hydrogen uptake at 3 atm (average) continuedfor 12 hours. The solution was then filtered on celite and the solventremoved under reduced pressure giving the title compound as a solid, m.p. 90-92°

1H-NMR(CDCl3): 5.29 (bs, 1H), 3.84 (bs, 1H), 3.05 (bs, 1H), 2.07 (m,2H), 1.9-1.4 (m, 12H), 1.44 (s, 9H).

INTERMEDIATE 48 1-tert-butoxycarbonyl-2-(2-adamantyl)pyrazolidin-3-one

To a solution of intermediate 47 (2 g) in dry dimethylformamide (20 ml)was added potassium carbonate (2.07 g) and after 15 min. chloropropionyl chloride (0.72 ml). The resulting mixture was stirred at roomtemperature for 3 hours then diluted with diethyl ether (100 ml). Thenit was washed with water (100 ml), ammonium chloride (sat., 100 ml) andbrine (100 ml). After drying the solvent was removed under reducedpressure and the mixture dissolved in dry dimethylformamide (20 ml).After the addition of potassium carbonate the solution was stirred for 3hours at room temperature The reaction mixture was then diluted withdiethyl ether (100 ml) and was washed with water (100 ml), ammoniumchloride (sat., 100 ml) and brine (100 ml). After drying the solvent wasremoved under reduced pressure to give a crude title compound which waspurified by silica gel column chromatography using cyclohexane/ethylacetate (3/1) as eluant to obtain the title compound (1.73 g).

1H-NMR(CDCl3): 4.08 (m, 1H), 3.91 (m, 2H), 2.6 (m, 2H), 2.52 (t, 2H),1.9-1.4 (m, 12H), 1.48 (s, 9H).

INTERMEDIATE 49 4.6-dichloro-3(5-oxo-2-(2-adamantyl)-1-tert-butoxycarbonyl-pyrazolidin-4-yl)-hydroxymethyl!1-tert-butoxycarbonyl-1H-indole2-carboxylicacid-tert-butyl ester

To a solution of intermediate 48 (0.386 g) in dry tetrahydrofuran (20ml) was added dropwise and at -78° C. a solution of lithiumbis(trimethylsilyl)amide 1 M in tetrahydrofuran (1.44 ml ). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution ofintermediate 14 (0.2 g) in dry tetrahydrofuran (1 OmI) was added. Thesolution was maintained at -20° for 30 min. then diluted withhydrochloric acid 0.1 M (50ml) and extracted with ethyl acetate (2×50ml). The collected organic phase was dried over sodium sulfate andconcentrated in vacuum. The crude compound was purified by silica gelcolumn chromatography using ethyl acetate/cyclohexane (1/9) as eluant togive the title compound (0.26 g) as a foam.

1H-NMR(DMSO):1.38(s, 9H), 1.50(s, 9H), 1.63(s, 9H), 1.6-1.8(m, 14H), 3.2-3.4(bs, 2H), 3.85(dt, 1H), 3.97(s, 1H), 5.61 (bs, 1H), 5.78(d, 1H),7.53(d, 1H), 7.90(d, 1H).

EXAMPLE 1 Methyl(E)4.6-dichloro3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylate

INTERMEDIATE 4 (700 mg) was suspended in ethanol (95 %) (10 ml),hydrochloric acid (10 ml, 6M) was added and the heterogeneous mixturerefluxed for 10 h. The suspension was cooled to room temperature and thesolid filtered, washed with further portions of 6M hydrochloric acid andfinally vacuum dried to yield the title compound (427 mg, ) as a whitesolid.

IR (nujol) Vmax (cm-1) 169(C═O), 1672 (C═O). ¹ H NMR (DMSO) 12.58 (bs),7.81 (d), 7.71 (t), 7.49 (d), 7.42 (t), 7.29 (d), 7.18 (t), 3.90 (s),3.88 (t), 3.53 (t), 264 (dt).

EXAMPLE 2(E)-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylicacid

Example 1(136 mg) and lithium hydroxide monohydrate (54 mg) weredissolved in ethanol (95 %) (5 ml) and the resulting solution refluxedfor 1.5 h. The solvent was evaporated and the residue treated at 50 °with 6M hydrochloric acid for 30 min, then at room temperature forfurther 30 min. The resulting white solid was filtered, washed andvacuum dried to yield the title compound (110 mg) as a white solid.

IR (nujol) Vmax (cm-1) 3281 (N--H), 1682 (C═O), 1630 (C═C). ¹ H NMR(DMSO) 13.9-13.3 (bs), 12.44 (s), 7.81 (d), 7.72 (t), 7.47 (d), 7.42(t), 7.26 (d), 7.18 (tt), 3.90 (s), 3.88 (t), 3.53 (t), 2.67 (td).

EXAMPLE 3 (E)4,6-dichloro-3-(2oxo-1 -phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt

Example 2 (100 mg) was suspended at room temperature in sodium hydroxidesolution (2.4 ml, 0.1 N) and the mixture was stirred until it becameonly slightly cloudy (approx 1 h). It was then lyophilized for 48 h togive the title compound (105 mg) as a white solid.

IR (nujol) Vmax (cm-1) 3302 (N--H). 1672 (C═O), 1639 (C═C). ¹ H NMR(DMSO) 12.0-11.0 (bs), 7.82 (t), 7.78 (d), 7.38 (t), 7.35 (d), 7.12 (t),7.04 (d), 3.79 (t), 2.77 (td).

EXAMPLE 4 Methyl(E)4,6-dichloro-3-(2-oxo-1-phenyl-piperidin-3-ylidenemethyl)-1H-indole-2carboxylate

INTERMEDIATE 5 (680 mg) was suspended in ethanol (95 %) (10 ml),hydrochloric acid (10 ml, 6M) was added and the heterogeneous mixturerefluxed for 10 h, The suspension was then cooled to room temperatureand the solid filtered, washed with further portions of 6M hydrochloricacid and finally vacuum dried to yield the title compound (490 mg,) as awhite solid.

IR (nujol) Vmax (cm-1) 3285 (N-H), 1682 (C═O), 1661 (C═O): ¹ H NMR(DMSO) 12.50 (bs), 7.88(t), 7.45 (d), 7.40(m), 724 (d), 7.24 (r) 3.87(s), 3.71 (t), 2.37 (td), 1.84 (m).

EXAMPLE 5 (E)4,6-dichloro-3-(2-oxo-1-phenyl-piperidin-3-ylidenemethyl)-1H-indole-2carboxylic acid

Example 4 (490 mg) and lithium hydroxide monohydrate (200 mg) weredissolved in ethanol (95 %) (20 ml) and the resulting solution refluxedfor 1.5 h. The solvent was evaporated and the residue treated at 50°with 6M hydrochloric acid for 30 min, then at room temperature forfurther 30 min. The resulting white solid was filtered, washed andvacuum dried to yield the title compound (400 mg) as a white solid.

IR (nujol) Vmax (cm-1) 3294 (N--H), 1670 (C═O), 1645 (C═O). ¹ H NMR(DMSO) 13.43 (bs), 12.36 (bs), 7.89 (t), 7.43 (d), 7.37 (m), 7.24 (m),7.21 (d), 3.71 (t), 2.39 (td), 1.85 (m).

EXAMPLE 6(E)4,6-dichloro-3-(2-oxo-1-phenyI-piperidin-3-ylidenemethyl)-1H-indole-2-carboxylicacid sodium salt.

Example 5 (100 mg) was suspended at room temperature in sodium hydroxidesolution (2.4 ml, 0.1 N) and the mixture was stirred until it becameonly slightly cloudy (approx 1 h). It was then lyophilized for 48 h togive the title compound (105 mg) as a white solid.

IR (nujol) Vmax (cm-1) 3305 (N--H), 1670 (C═O)1645 (C═O). ¹ H NMR (DMSO)11.6 (bs), 8.00 (t), 7.38 (m), 7.34 (d), 7.22 (tt), 7.03 (d), 3.68 (t),2.46 (td), 1.81 (m).

EXAMPLE 7 (E) 3 (1-tert-butoxycarbonyl-3-oxo-2phenyl)pyrazolidin-4-ylidenemethyl!-4.6-dichloro-1H-indole-2-carboxylic acid

To a solution of intermediate 7(1.6 g) in dry tetrahydrofuran (90 ml)was added dropwise and at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (6.7 ml ). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution ofintermediate 8 (2 g) in dry tetrahydrofuran (60 ml) was added. Thesolution was maintained at -20° for 30 min. then warmed up to 25° for 4hrs. The solution was diluted with diethyl ether (300 ml) and washedwith 0.1 M hydrochloric acid (200 ml). The aqueous solution wasextracted with diethyl ether (100 ml) and the collected organic phasewas dried and concentrated in vacuum. The crude compound wascrystallized from ethyl acetate/n-hexane to give the title compound(0.92g). mp.=182° 1719, 1688(C═O), 1659. ms ((m/z): 502.

EXAMPLE 8 (E)4,6-dichloro-3-(5oxy-1-phenyl-pyrazolidin-4ylidenemethyl)-1H-indole-2-carboxylicacid sodium salt

The compound of example 7 (0.255 g) was dissolved in dry dichloromethane(5 ml) and trifluoroacetic acid (5 ml). The resulting solution wasstirred at 25° for 1 hr then concentrated in vacuo Trituration of theresidue with diethyl ether gave the corresponding acid intermediate(0.177 g). This product (0.155 g) was suspended in water and sodiumhydroxide 0.1M was added (3.77 ml). The heterogeneus solution wasstirred at 25° for 2 hrs then freeze-dried to obtain the title compound(0.160 g)

1H-NMR(DMSO): 3.94(d, 2H), 6.26(t, 1H), 7.08(m+s, 2H), 7.37(m+s, 3H),7.83(bs, 1H), 7.91 (m, 2H). I.R.(cm-1)=3177(NH), 1674(C═O), 1595(C═C).ms (m/z): 494, 402.

EXAMPLE 9 (E)3- (1-tert-butoxycarbonyl-2-(4tert-butoxycarbonylamino)phenyl!-3-oxo) pyrazolidin-4-ylidenemethyl!-4,6dichloro-1H-indole-2-carboxylic acid

To a solution of intermediate 12 (0.47 g) in dry tetrahydrofuran (15ml)was added dropwise, at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (2.6 ml). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution of4,6-dichloro-3-formyl-1- N-tert-butoxycarbonyl-!-1H-indole-2carboxylicacid ethyl ester (0.436 g) in dry tetrahydrofuran (10 ml) was added. Thesolution was maintained at -20° for 30 min. then warmed up to 25°. for 4hrs. The solution was-diluted with diethyl ether (200 ml) and washedwith hydrochloric acid 0.1M (100 ml). The aqueous solution was extractedwith diethyl ether (100 ml) and the combined organic phase was dried andconcentrated in vacuo. The crude compound was crystallized from ethylacetate/n-hexane (1/2) to give the title compound (0.30 g). mp.=220°dec.

I.R.(cm-1): 3418-3281(NH, OH), 1736, 11713(C═O), 1676, 1612(C═C). ms(m/z): 505, 415, 242.

EXAMPLE 10 (E) 4,6dichloro-3-(5-oxo-1-(4-aminophenyl))pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid hydrochloride salt

The compound of example 9 (0.830 g) was dissolved in methanol (60 ml)and hydrogen chloride was bubbled through the solution for 5 min. Theresulting solution was stirred at 25° for 2 hrs then concentrated invacuo. Trituration of the residue with diethyl ether gave the titlecompound (0.450 g).

1H-NMR(DMSO): 3.86(d, 2H), 7.28(d, 1H), 7.38(d, 2H), 7.47(d, 1H),7.74(t, 1H), 8.00(d, 2H)- 10.0(b, 3H), 12.5(bs, 1H)I.R.(cm-1)=3439-3325(NH), 1730-1676(C═O), 1612(C═C). ms (m/z): 417.

EXAMPLE 11 (E)4,6-dichloro-3(5-oxo-1(4-aminophenyl)pyrazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt

Example 9 (0.200 g) was dissolved in dry dichloromethane (20 ml) andtrifluoroacetic acid (6 ml). The resulting solution was stirred at 25°for 2 hrs then concentrated in vacuo. The residue was suspended in water(5 ml), 1 M sodium hydroxide (1 ml) was added and after 5 minutes thesolution was acidified with 1M hydrochloric acid until pH =3. Ethylacetate (3×100 ml) was added and the organic layers were collected anddried. The solvent was evaporated by distillation under reduced pressureTrituration of the residue with diethyl ether gave the correspondingacid intermediate (0.060 g,). This product (0.01 9 g) was suspended inwater and 0.1M sodium hydroxide was added (0.45 ml). The homogeneoussolution was stirred at 5° for 30 minutes then freeze-dried to obtainthe title compound (0.017 g).

1H-NMR(DMSO): 3.82(d, 2H), 6.56(d, 2H), 7.21 (d,₁ I H), 7.42(d, 1H),7.54(d+s, 2H+1H), 11.5-13.0(bm,₁ H). I.R.(cm-1)=3440-2680(NH),1734(C═O), 1587(C═C).

EXAMPLE 12 (Z) 4,6-Dichloro-3-(2,5dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-l H-indole-2-carboxylic acid

Intermediate 16 (140 mg) was suspended in formic acid (10 ml) andstirred at room temperature for 10 hs. The solvent was removed underreduced pressure to give the title compound as a cream solid (92 mg, mp.>250°)

IR (Nujol) ν_(max) (cm-1) 3186 (N--H), 1769 (C═O), 1732 (C═O) and 1691(C═O). ¹ H-NMR (DMSO) 12.42 (bs), 10.70 (bs), 7.49 (td), 7.44 (d), 7.43(d), 7.40 (tt), 7.25 (d) and 7.04 (s).

EXAMPLE 13 (E)4,6-Dichloro-3-(2,5dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2-carboxylicacid allyl ester

Intermediate 19 (360 mg) was suspended in formic acid (20 ml) andstirred at room temperature for 5 h. The solvent was removed underreduced pressure to give the title compound as a yellow solid (296 mg,mp. >250°).

IR (Nujol) ν_(max) (cm- 1) 3261 (N--H), 1757 (C═O), 1720 (C═O) and 1668(C═C). ¹ H-NMR (DMSO) 12.47 (bs), 10.98 (bs), 7.45 (td), 7.44 (d), 7.35(ttO, 7.28 (dd), 7=22 (d), 6.82 (s), 5.94 (m), 5.35 (m) and 4.76 (d).

EXAMPLE 14 (E)4,6Dichloro-3-(2.5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2-carboxylicacid

To a solution of example 13 (290 mg) in dry THF (10 ml)5,5-dimethyl-1,3-cyclohexandione (98 mg) and palladium tetrakistriphenylphosphine (18.4 mg) were added- The mixture was stirred at roomtemperature for 2 hs then diluted with ethyl acetate and quenched withwater. The solvent was removed under reduced pressure, the precipitatedissolved in diethyl ether and extracted with a solution of Na₂ CO₃ (5%). The aqueous solution was acidified giving a precipitate which wascollected by filtration to furnish the title compound as a yellow solid(147 mg mp. >250°).

IR (Nujol) ν_(max) (cm-1) 3335 (N--H), 1763-1724 (C═O) and 1678-1664(C═O). ¹ H-NMR (DMSO) 12.35 (bs), 10.95 (bs), 7.50-7.28 (m), 7.20 (d)and 6.83 (s).

EXAMPLE 15 (E) 3(1-tert-butoxycarbonyl-3-oxo-2-phenyl)pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1H-indole-2-carboxylic acid tert-butyl ester

A suspension of example 7 (0:7 g) in benzene was heated at reflux andthen N,Ndimethylformamide-di-tert-butyl acetal (1.5ml) was addeddropwise. The resultant solution w,as heated at reflux for 30 min. thendiluted with ethyl acetate (100 ml), washed with sodium bicarbonate(sat) (100 ml), brine (100 ml), dried and concentrated in vacuo toafford the crude title compound (0.7 g). T.I.c. EA/CH (6124), R_(f)=0.8.

1H-NMR(CDCl₃): 1.23(s, 9H), 1.57(s, 9H), 4.60(d, 2H), 7.14(m, 1H),7.18(d, 1H), 7.35(d, 1H), 7.40(m, 2H), 7.70(m, 2H), 7.93(t, 1H),9.15(bs, 1

EXAMPLE 16 3- (2-(4-amino-phenyl)-1-tert-butoxycarbonyl-3-oxo-pyrazolidin-4-ylidenemethyl!-4,6dichloro-1H-indole-2-carboxylicacid

Example 9 (0.110 g) was dissolved in dry dichloromethane (11 ml) andtrifluoroacetic acid (0.55ml). The resulting solution was stirred at 0°for 3 hrs then concentrated in vacuo. Trituration of the residue withdiethyl ether (6 ml) gave the corresponding title compound as a brownsolid (0.070 g).

1H-NMR (DMSO): 1.22(s,9H), 4.50(d,2H), 6.98(d,2H), 7.30(d₁ H), 7.43(d,2H) 7.48(d, 1H), 7.76(t, 1H), 12.6(s, 1H).

EXAMPLE 17 3- 2-(4-Acetylamino)-phenyl)-1-tert-butoxycarbonyl-3-oxo-pyrazolidin-4-ylidenemethyl!4,6dichloro-1H-indole-2-carboxylicacid.

To a solution of example 16 (0.200 gr) in dry tetrahydrofuran (5 ml)under nitrogen was added triethylamine (0.115 ml). After 5 minutes at0°, chloroacetyl chloride (0.040 ml) was added dropwise to the stirredsolution. The reaction mixture was allowed to warm up to roomtemperature over 2 hrs and then a solution of 5 % sodium bicarbonate (30ml) was added. The reaction-mixture was extracted with ethyl acetate(3×20) and the combined organic phases dried and concentrated in vacuo.The crude title compound was purified by silica gel flash columnchromatography (dichloromethane:methanol:acetic-acid =90:5:5) to givesthe title compound a yellow solid (0.023 g).

I.R.(cm-1, Nujol):3500-2500(OH,NH), 1668(C═O), 1607(C═O,C═C).

EXAMPLE 18 4.6-Dichloro- 3-5-oxo1-(4-acetylamino-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid

Example 17 (0.023 g) was dissolved in dry dichloromethane (5ml) and 20trifluoroacetic acid (5ml). The resulting solution was stirred at 25°for 2 hrs then concentrated in vacuo. Trituration with diethyl ether (5ml) afforded title compound as a pale brown solid (0.030 g).

1H-NMR(DMSO):2.02(s,3H), 3.83(m,2H), 6.40(s,1H), 7:26(d,1H),7.45(d,1H7.58(m,2H), 7.67(t, 1H), 7.82(m,2H), 9.95(s, 1H), 12.44(s, 1H), 13.7(s,1H). I.R.(cm-1, Nujol):3500-2500(OH--NH), 1678-1650(C═O), 1601(C═C).

EXAMPLE 19 3-1-tert-butoxycarbonyl-3-oxo-2(4-ureido-phenyl)-pyrazolidin-4-ylidenemethyl!-4,6dichloro-1H-indole-2carboxylic acid

To a solution of example 16 (0.070 g) in tetrahydrofuran (4 ml) undernitrogen at room temperature was added trimethylsilylisocyanate (0.080ml)-The solution was refluxed for 4 hrs, after which time the productwas seen to precipitate from the solution. The solid was filtered offand washed with tetrahydrofuran (10 ml) affording the title compound asan orange solid. (0.042 g).

1H-NMR (DMSO):1.22(s,9H), 4.52(m,2H), 5.87(s,2H), 7.30(s,1H),7.45(m,4H), 7.50(m, 1H), 7.80(s,1H), 8.65(s1H), 12.5(s, 1H). I.R.(cm-1,Nujol):3489-3341(NH).

EXAMPLE 20 4,6-Dichloro-3-5-oxo-1-(4-ureido-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid

Example 19 was dissolved in dry dichloromethane (1 ml) andtrifluoroacetic acid (2 ml). The resulting solution was stirred at 25°for 2 hrs then concentrated in vacuo. Trituration with diethyl ether (5ml) afforded the title compound as a red solid (0.030 g).

1H-NMR(DMSO):3.81(m,2H), 5.82(s,2H), 6.36(s,1H), 7.25(d, -H),7.39-7.45(m,3H), 7.65(t.1H), 7.75(m,2H), 8.53(s,1H), 12.43(s,1H),13.71I.R.(cm-1, Nujol):3500-2600(OH,NH).

EXAMPLE 21 3-1-tert-butoxycarbonyl-2-(4methylsulfamidophenyl)-3-oxo-pyrazolidin4-ylidenemethyl!-4,6-dichloro-1H-indole-2-carboxylicacid

To a solution of intermediate 23 (0.100 g) in dry tetrahydrofuran (5ml)was added dropwise, at -78°, a 1M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.53 ml). The reactionmixture was allowed to warm up to =20° over 30 min., then a solution of4,6-dichloro-3-formyl-1 N-tertbutoxycarbonyl!-1H-indole-2-carboxylicacid ethyl ester (0.100 g) in dry tetrahydrofuran (4 ml) was added. Thesolution was maintained at -20° for 30 min. then warmed up to 25° over 4hrs. The solution was diluted with diethyl ether (20 ml) and washed with0.1M hydrochloric acid (1Oml). The aqueous solution was extracted withdiethyl ether (15ml) and the combined organic phases were dried andconcentrated in vacuo. The crude compound was purified by silica gelflash column chromatography (dichloromethane: methanol: aceticacid=90:5:5) to the title compound (0.035 g).

EXAMPLE 22 4,6Dichloro-3-1-(4-methylsulfamidophenyl)-5-oxo-pyrazolidin4-ylidenemrthyl!-1H-indole-2-carboxylicacid

Example 21 (0.035 g) was dissolved in dry dichloromethane (6m1) andtrifluoroacetic acid (2 ml). The resulting solution was stirred at 250for 2 hrs then concentrated in vacuo. Trituration with ethyl acetate (5ml) afforded the title compound as a yellow solid (0.010 g).

1H-NMR (DMSO):2.94(s,3H), 3.83(bm,2H), 6.40(bs,IH), 7.22(d,2H), 7.26(d,₁H), 7.45(d, 1H), 7.68(t, 1H), 7.86(d,2H), 9.67(s,1H), 12.48(bs, 1H).I.R.(cm-1, Nujol):3186(NH), 1680(C═O), 1640(C═C).

EXAMPLE 23 (E) 3 (2-methyl-5-oxo-1-phenyl)pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1H-indole-2-carboxylic acid

To a solution of intermediate 25 (0.365 g) in dry tetrahydrofuran (1 Om) was added dropwise and at =78° a solution of lithiumbis(trimethylsilyl)amide 1 M in tetrahydrofuran (1.33ml). The reactionmixture was allowed to warm up to =200 in 30 min., then a solution ofintermediate 8 (0.2 g) in dry tetrahydrofuran (1 Oml) was added. Thesolution was maintained at =20° for 30 min. then warmed up to 25° for 4hrs. The solution was diluted with diethyl ether (300 ml) and washedwith hydrochloric acid 0.1M (200 ml)- The aqueous solution was extractedwith diethyl ether (1 00 ml) and the collected organic phase was driedand concentrated in vacuo The crude compound was triturated with diethylether to give the title compound (0.06 g).

1H-NMR (DMSO): 3.31 (s, 3H), 3.63(bs, 1H), 4.08(bs,₁ H), 7.16(t, 1H).1tH), 7.42(t, 2H), 7.45(d, IH), 7.83(s, IH), 7.84(d, 2H), 12.48(s, 1H),13.75(bs, 1H). I.R.(cm-1): 3244(NH), 1676(C═O), 1653(C═C).

EXAMPLE 24 4,6-dichloro-3-(3-oxo-2-phenyl-isoxazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid

To a solution of intermediate 27 (047Sg) in dry tetrahydrofuran (20 ml)was added dropwise and at -78° C. a solution of lithiumbis(trimethylsilyl)amide 1 M in tetrahydrofuran (3.2 ml). The reactionmixture was allowed to warm up to -20° in 30 min., then a solution ofethyl 4,6 dichloro=34formyl-1-butoxycarbonyl 1indole-2carboxylate (0.94g) in dry tetrahydrofuran (20 ml) was added. The solution was maintainedat -20° for 30 min. then warmed up to 25° for 4 hrs. The solution wasdiluted with diethyl ether (300 ml) and washed with hydrochloric acid0.1M (200 ml). The aqueous solution was extracted with diethyl ether(100 ml) and the collected organic phase was dried and concentrated invacuum. The crude compound was purified by silica gel columnchromatography using ethyl acetate/cyclohexane as eluant to give thecrude title compound (0.16 g) with T.I.c. dichloromethane/methanol 2713,R_(f=) 0.3

EXAMPLE 25 4,6-Dichloro-3-(3-oxo-2-phenyl-isoxazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid tert butyl ester

The product of Example24 was treated withN,Ndimethylformamide-di-tert-butyl acetal (0.44ml ) in benzene (1 5 ml).The resultant solution was heated at reflux for 30 min. thenconcentrated in vacuo to afford the crude compound that was purified bysilica gel column chromatography using ethyl acetate/cyclohexane aseluant to give the title compound (0.03 g). T.I.c. ethylacetate/cyclohexane (1/2), R_(f=) 0.6. m.p.=120° C.

1H-NMR (CDCl₃): 159(s, 9H), 5.04(d, 2H), 7.17(t, 1H), 7.18(d, 1H),7.34(d, 7.40(t, 2H), 7.85(d, 2H), 7.91 (t, 1H), 9.05(bs, 1H).

EXAMPLE 26 4,6-Dichloro-3-(3-oxo-2-phenyl-isoxazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid

Example 25 (0.025 g) was dissolved in dry dichloromethane (3ml) andtrifluoroacetic acid (2 ml). The resulting solution was stirred at 25°for 1 hr then concentrated in vacuo. Trituration with isopropanol of theresidue gave the title compound as a solid (0.014 g) m.p.>250°.

1H-NMR (DMSO): 5.07(d, 2H), 7.20(t, 1H), 7.30(d, 1H), 7.45(t, 2H),7.47(d, 1H), 7.74(dd, 2H), 7.85(t, 1H), 12.59(s, 1H), 13.89(bs, 1H).I.R.(cm-1): 3304(NH), 1672(C═O), 1645(C═C). ms (m/z): 403.

EXAMPLE 27 (E) 4,6dichloro-3(5-oxo-1-(3-aminophenyl))pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid hydrochloride salt

To a solution of intermediate 30 (0.03 g) and intermediate 31 (0.039) inmethanol (30 ml) was bubbled hydrogen chloride at 0° for 5 min. Theresulting solution was stirred at 25° for 1 hrs then concentrated invacuo- Trituration of the residue with diethyl ether gave the titlecompound (0.01 g). 1H-NMR(DMSO): 5.85(d, 2H), 7.08(d, 1H), 7.27(d, 1H),7.47(d, 1H), 7.48(t 7.76(t, 1H), 7.83(d, I H), 8.02(s, 1H), 9.510.5(b,3H), 12.5(bs, 1H) I.R.(cm-1): 3400-3200(NH and OH), 1711 (C═O).

EXAMPLE 28 (E)4,6dichloro-3-(2.5-dioxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylicacid

A suspension of intermediate 32 (295 mg) in formic acid (40 ml) wasstirred at room temperature for 6 hours the the solvent removed underreduced pressure. The residue was triturated with ethyl acetate andfiltered to give the title compound as cream solid. (148 mg, mp.>250°).IR (Nujol) ν_(max) (cm-1) 3204 (N--H), 1705 (C═O). 1H-NMR (DMSO) 14--13(bs), 12.6 (s), 8.08 (t), 7.51 (tt), 7.475 (d), 7.43 (m), 7.38 (d), 7.30(d), 3.38 (d).

EXAMPLE 29 (E) 3(1-tert-butoxycarbonyl-3-oxo-2-phenyl)-tetrahydro-pyridazin-4-ylidenemethyl!-4,6dichloro-1H-indole-2-carboxylicacid

To a solution of intermediate 33 (0.85 g) in dry tetrahydrofuran (8 ml)was added dropwise and at -50° a solution of lithiumbis(trimethylsilyl)amide I M in tetrahydrofuran (2 ml) and the reactionmixture was stirred at =20/140 for 30 min. Then the solution was cooledat 40° and a solution of intermediate 8 (0.33 g) in dry tetrahydrofuran(7 ml) was added. The solution was warned up to 25° and stirred for 3hrs then it was diluted with ethyl acetate (300 ml) and washed withhydrochloric acid 2M (20 ml). and brine (2×30 ml). The collected organicphase was dried and concentrated in vacuum. The crude compound wascrystallized from ethyl acetate/n-hexane (5 ml/8 ml) at 0° C. to givethe title compound (0.2 g). mp.>240°.

1H-NMR(DMSO): 1.28(s, 9H), 2.56 (bs, 1H), 3.84 (bs, 2H), 7.19(tt, 1H),7.19 (d, 1H), 7.37(t, 2H), 7.46(d, 1H), 760(dd, 2H), 8.0(t, 1H),12.8(bs, 1H), 13.5(bs,1H).

EXAMPLE 30 (E)4,6-dichloro-3-(3-oxo-2phenyl-tetrahydro-pyridazin-4-ylidenemethyl)-1H-indole-2-carboxylicacid

To a solution of example 29(0.117 g) in dichloromethane (10 ml) wasadded dropwise trifluoroacetic acid (3 ml) at 0° C. The reaction mixturewas warmed up to 25° and stirred for 2hr then concentrated in vacuo. Theresidue was dissolved in ethyl acetate (30 ml), basified with a 5 %solution of sodium hydrogen carbonate and acidified with a saturatedsolution of ammonium chloride. The brganic phase was dried andconcentrated in vacuo. The residue was triturated in ethylacetate/diethyl ether (2 ml/1 ml) to give the title compound (0.0469g)as a pale yellow powder mp.>250°.

1H-NMR(DMSO): 3.10(m, 2H),3.35(m, 2H), 6.02(t, I H), 7.12(t, 1Hj,7.22(d, 1H), 7.33(t, 2H), 7.43(d, 1H), 7.63(d, 2H), 8.00(t, 1H),12.36(s, IH), 13.50(bs, 1

EXAMPLE 31 (E) 4,6.-dichloro-3(5oxo-1-(2-quinolinyl)pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacic hydrochloride salt

To a solution of intermediate 38 (0.115) in methanol (15 ml) was bubbledhydrogen chloride at 25° for 5 min. The resulting solution was stirredat 25° for 4 hrs then concentrated in vacuo- Trituration of the residuewith diethyl ether gave the title compound (0.35 g). m.p.>240°.

EXAMPLE 32 (E) 4,6dichloro-3(5-oxo-1-(2-pyridyl)pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid hydrochloride salt

To a solution of intermediate 42 (0.055 g) in methanol (15ml) wasbubbled hydrogen chloride at 25° for 5 min. The resulting solution wasstirred at 25° for 6 hrs then concentrated in vacuo. Trituration of theresidue with diethyl ether gave the title compound (0.02 g). m. p.>240°.

EXAMPLE 33 (E)3-1-tert-butoxycarbonyl-2-(1-naphthyl)-3-oxo-!pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1-tert-butoxycarbonyl-1H-indole-2-carboxylic acidtert butyl ester

To a solution of intermediate 45 (0.18 g) in dry tetrahydrofuran (10ml)was added dropwise, at -78° a solution of lithiumbis(trimethylsilyl)amide 1M in tetrahydrofuran (0.58ml ). The reactionmixture was allowed to warm up to -20° in 30 min., then the reactionmixture was cooled at -40° and a solution of 4,6-dichloro-3-formyl-1-N-tert-butoxycarbonyl!-1H-indole-2carboxylic acid tert butyl ester (0.2g) in dry tetrahydrofuran (6 ml) was added. The solution was maintainedat -40° for 20 min. then slowly warmed up to 250 for 2 hrs. The solutionwas poured in a saturated ammonium chloride solution and extracted withethyl acetate (200m1). The organic layer was washed with water, driedand concentrated in vacuo. The crude compound was purified by silica gelcolumn chromatography using diethylether/cyclohexane (3/7) as eluant togive the title compound (0.030 g) as a yellow wax, T.I.c.diethylether/cyclohexane (1/2),

R_(f=) 055 I.R.(cm-1)=3500-2700(NH), 1720-1690(C═O;

EXAMPLE 34 (E) 4,6-dichloro-3(5-oxo-1(1-naphthyl)-pyrazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid

Example 33 (0.030 g) was dissolved in dry dichloromethane (5ml) andtrifluoroacetic acid (4ml ). The resulting solution was stirred at 25°for 1 hr then concentrated in vacuo. Trituration of the residue withdiethyl ether gave the title compound (0.010 g), m.p. 200° dec.

¹ H-NMR(DMSO): 14.2-12.5 (broad, 1H), 12.46 (s, 1H), 8.04, 7.90 (m, 3H),7.76 (t, 1H), 7.66-7.56 (m, 4H), 7.50 (d, 1H), 7.30 (d, 1H), 6.60 (s,1H), 4.04 (d, 2H); I.R.(cm-1)=3410-3184(OH,NH), 1707-1686(C═O),1659(C═C).

EXAMPLE 35 (E) 3- (1-tert-butoxycarbonyl-3-oxo-2-(2-adamantyl)pyrazolidin-4-ylidenemethyl!-4,6-dichloro-1H-indole-2-carboxylic acid-tert-butyl ester

To a solution of intermediate 49 (0.144 g) in tetrahydrofuran (1OmI) wasadded dropwise and at 0° a solution of lithium bis(trimethylsilyl)amide1 M in tetrahydrofuran (0.2 ml). The reaction mixture was allowed towarm up to 25° for 2 hrs then diluted with hydrochloric acid 0.1M (50ml) and extracted with diethyl ether (2×50 ml). The collected organicphase was dried over sodium sulfate and concentrated in vacuum. Thecrude compound was purified by silica gel column chromatography usingethyl acetate/cyclohexane (1/9) as eluant to give the title compound(0.02 g) as a foam.

1H-NMR(CDCl3): 0.75-2.00(m+s+s, 30H), 2.75(m, 2H), 4.22(bs)-4.34(d) 3H!,7.13(d)-7.33(d)-7.69(t), 3H!, 9.15(bs, 1H).

EXAMPLE 36 (Z) 4,6-dichloro-3-5-oxo-1-(2adamantyl)pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylicacid

Example 35 (0.02 g) was dissolved in dry dichloromethane (1 ml) andtrifluoroacetic acid (1 ml). The resulting solution was stirred at 25°for 1 hr then. concentrated in vacuo. Trituration with diethyl ether ofthe residue gave the title compound (0.003 g), m.p. 190° dec.a

1H-NMR(DMSO): 1.50-1.92(m 10H), 2.20-2.32(m, 4H), 3.67(d, 2H), 4.02(bs,1H), 5.7(b, 1H), 7.26(d; 1H), 7.46(d)-7.51(t), 2H!, 12.41(bs, 1H),13.56(bs, 1 H).

EXAMPLE 37 (Z)4,6-dichloro-3(5-oxo-1-phenyl-pyrazolidin-4-ylidenemethyl)-1H-indole-2-carboxylicacid

The intermediate 21 (0.125 g) was dissolved in dry dichloromethane (5ml)and trifluoroacetic acid (5 ml). The resulting solution was stirred at25° for 1 hr then concentrated in vacuo. Trituration with diethyl etherof the residue gave title. compound acid (0.041 g). 1H-NMR(DMSO):4.15(d, 2H), 6A48(bm, 1H), 7.05(m, 1H), 7.14(d, 1H), 7.18(t, 1H),7.30(t, 2H), 7.41 (d, 1H), 7.74(d, 2H), 12.24(s, 1H), 13.31 (bs, 1H).

PHARMACY EXAMPLES A Capsules/Tablets

    ______________________________________                                        Active ingredient  200.0      mg                                              Starch 1500        32.5       mg                                              Microcrystalline Cellulose                                                                       60.0       mg                                              Croscarmellose Sodium                                                                            6.0        mg                                              Magnesium Stearate 1.5        mg                                              ______________________________________                                    

The active ingredient is blended with the other excipients. The blendcan be used to fill gelatine capsules or compressed to form tabletsusing appropriate punches. The tablets can be coated using conventionaltechnqiues and coatings.

    ______________________________________                                        Active ingredient  200.0      mg                                              Lactose            100.0      mg                                              Microcrystalline Cellulose                                                                       28.5       mg                                              Povidone           25.0       mg                                              Croscarmellose Sodium                                                                            6.0        mg                                              Magnesium Stearate 1.5        mg                                              ______________________________________                                    

The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium- The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

C. Injection Formulation

    ______________________________________                                        Active ingredient      0.1-7.00 mg/ml                                         Sodium phosphate       1.0-50.00 mg/ml                                        NaOH qs desidered pH (range 3-10)                                                                    1 ml                                                   water for injection qs to                                                     ______________________________________                                    

The formulation may be packed in glass (ampoules) with a rubber stopper(vials, syringes) and a plastic/metal overseal (vials only).

D. Dry Powder for constitution with a suitable vehicle

    ______________________________________                                        Active ingredient:   0.1-100.00 mg                                            Mannitol qs to       0.02-5.00 mg                                             ______________________________________                                    

packed in glass vials or syringes, with a rubber stopper and (vialsonly) a plastic metal overseal.

E. Inhalation Cartridges

    ______________________________________                                                           mg/cartridge                                               ______________________________________                                        Active ingredient (micronised)                                                                   5.00                                                       Lactose to         25.00                                                      ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range prior to blending with normal tabletting gradelactose in a high energy mixer. The powder blend is filled into a properunit dose container as blister or, capsule for use in a suitableinhalation or insufflation device.

The affinity of the compound of the invention for strychnine insensitvieglycine binding site was determined using the procedure of Kishimoto H.et al J. Neurochem 1981, 37,1015-1024. The pKi values obtained withrespresentative compounds of the invention are given in the followingtable.

    ______________________________________                                               Example No.                                                                           pKi                                                            ______________________________________                                               3       7.29                                                                  6       7.31                                                                  8       8.0                                                                   10      7.83                                                                  12      7.43                                                                  14      7.13                                                                  18      7.7                                                                   20      7.69                                                                  22      7.66                                                                  23      7.46                                                                  26      7.12                                                                  27      7.7                                                                   28      7.38                                                                  34      7.31                                                           ______________________________________                                    

The ability of compounds of the invention to inhibit NMDA inducedconvulsions in the mouse was determined using the procedure ofChiamulera C et al. Psychopharmacology 1990, 102, 551-552. In this testthe ability of the compound to inhibit the generalized seizures inducedby an intracerebroventricular injection of NMDA in mice was examined ata number of dose levels. From these results the dose required to protect50 % of the animals from the convulsive action of the NMDA wascalculated. This expressed as mg/kg is referred to as the ED₅₀ value.

Representative results obtained for compounds of the invention whengiven by intravenous (IV) and oral (po) administration are given in thefollowing table.

    ______________________________________                                                         ED.sub.50                                                                            ED.sub.50                                             Ex. No.          i.v    po                                                    ______________________________________                                        3                0.08   3.83                                                  6                0.09   7.50                                                  8                0.1    1.70                                                  10               0.1    1.7                                                   ______________________________________                                    

The compounds of the invention are essentially non toxic attherapeutically useful doses. Thus for an example the compound ofExample 8 showed no adverse affects when administered to anaesthetisedcats or conscious dogs at doses up to 24 mg/kg.

We claim:
 1. A compound of formula (I) ##STR11## or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO₂ R₂ or COR₂ wherein R₂ represents hydroxy, methoxy, amino, alkylamino, or dialkylamino; m is zero or an integer 1 or 2;R₁ represents a cycloalkyl, bridged cycloalkyl, heteroaryl, bridged heterocyclic or optionally substituted phenyl or fused bicyclic carbocylic group; A represents a C₁₋₄ alkylene chain or the chain (CH₂)_(p) Y(CH₂)_(q) wherein Y is O, S(O)n or NR₃ and which chains may be substituted by one or two groups selected from C₁₋₆ alkyl optionally substituted by hydroxy, amino, alkylamino or dialkylamino, or which chains may be substituted by the group ═O; R₃ represents hydrogen, alkyl or a nitrogen protecting group; n is zero or an integer from 1 to 2; p is zero or an integer from 1 to 3; q is zero or an integer from 1 to 3 with the proviso that the sum of p=q is 1, 2 or
 3. 2. A compound as claimed in claim 1 wherein m is 2 and R is chlorine at the 4 and 6 positions in the indole nucleus.
 3. A compound as claimed in claim 1 wherein A is a chain selected from --(CH₂)₂ --, --(CH₂)₃ --, --CH₂ CO--, --CH₂ NH--, --CH₂ NCH₃ --, --(CH₂)₂ NH--, --NHCO-- or --CH₂ O--.
 4. A compound as claimed in claim 1 wherein A is the chain --CH₂ NH--.
 5. A compound as claimed in claim 1 wherein R₁ is a group selected from optionally substituted phenyl, 1-naphthyl, 2pyridyl, 2quinolinyl, cyclohexyl or 2-adamantyl.
 6. A compound as claimed in claim 1 wherein R₁ is optionally substituted phenyl.
 7. A compound as claimed in claim wherein R₁ is phenyl.
 8. The trans isomer of a compound as claimed in claim
 1. 9. (E) 4,6-dichloro-3-(5-oxo-1-phenyl-pyrazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid and physiologically acceptable salts or metabolically labile esters thereof.
 10. The compounds:(E) 4,6-dichloro-3-(2-oxo-1-phenyl-piperidin-3-ylidenemethyl)-1H-indole2-carboxylic acid; (E) 4,6-dichloro-3- (5-oxo-1-(4-aminophenyl))pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid; (Z) 4,6-Dichloro-3-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid; (E) 4,6-Dichloro-3-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl)-1H-indole-2-carboxylic acid; 4,6-Dichloro-3- 5-oxo-1-(4-acetylamino-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid; 4,6-Dichloro-3- 5-oxo-1-(4-ureido-phenyl)-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid;
 4. 6-Dichloro-3- 1-(4-methylsulfamidophenyl)-5-oxo-pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid;4,6-Dichloro-3-(3-oxo-2phenyl-isoxazolidin-4-ylidene methyl)-1H-indole-2-carboxylic acid; (E) 4,6-dichloro-3- (5-oxo-1-(3-aminophenyl))pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid; (E) 4,6-dichloro-3-(2,5-dioxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid; (E) 4,6-dichloro-3- (5-oxo-1-(1-naphthyl)pyrazolidin-4-ylidenemethyl!-1H-indole-2-carboxylic acid; and physiologically acceptable salts metabolically labile esters thereof.
 11. A pharmaceutical composition comprising a compound as claimed in claim 1 in admixture with one or more physiologically acceptable carrier or excipients.
 12. A method of treatment of a human for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in claim
 1. 13. A process for preparing the compounds as defined in claim 1 which comprises:a) a process for preparing compounds of formula (I) wherein the chain A has the meanings defined in claim 1 with the proviso that A is not NHCO-- which comprises reacting the aldehyde (II) ##STR12## wherein R has the meanings defined in formula (I) or is a protected derivative thereof, R₄ is a carboxyl protecting group and R₅ is a nitrogen protecting group, with the cyclic amide of formula (III) wherein R₁ and A have the meanings defined in formula (I) (with the proviso that A is not --NHCO) or are protected derivatives thereof, in the presence of a base; b) a process for the preparation of compounds of formula (I) wherein A is the chain --NHCO-- which comprises reacting the aldehyde (III), or a protected derivative thereof with the glycine derivative (VIII) ##STR13## wherein R₁ is a group as defined in claim 1 or a protected derivative thereof and R₆ and R₇ independently represent C₁₋₄ alkyl, c) a process for preparing a compound of formula (I) wherein A is CH₂ CO by reacting the aldehyde (II) or a protected derivative thereof with the phosphorane derivative (IX) ##STR14## wherein R₁ has the meanings defined in formula (I) or is a protected derivative thereof in the presence of a base; d) a process for preparing compounds of formula (I) wherein the exocyclic bond is in the cis configuration which comprises irradiating the corresponding trans isomer or a protected derivative therewith with UV light; and if necessary or desired subjecting the resulting compound to one or more of the following operations:(i) removal of one or more protecting groups, (ii) isolation of the compound as a salt thereof, (iii) conversion of a compound of formula (I) or a salt thereof into a metabolically labile ester thereof or, (iv) conversion of a compound of formula (I) into a physiologically acceptable salt thereof.
 14. (E)-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid.
 15. (E)-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt.
 16. A pharmaceutical composition comprising a compound as claimed in claim 14 in admixture with one or more physiologically acceptable carriers or excipients.
 17. A pharmaceutical composition comprising a compound as claimed in claim 15 in admixture with one or more physiologically acceptable carriers or excipients.
 18. A method of treatment of a human for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in claim
 14. 19. A method of treatment of a human for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in claim
 15. 